Allergen-containing dosage form

FIELD: medicine.

SUBSTANCE: present invention concerns medical products, particularly a pharmaceutical product for introduction of allergen that contains high-soluble solid dosage form introduced through tunica mucosa of mouth and containing matrix made by freeze drying from the solution containing 3-6.5 wt % pre-gelled starch and 3-5.5 wt % mannitol, or from the solution containing 2-10 wt % fish gelatine and 1-10 wt % mannitol; and allergen. Besides, invention concerns the method for making the specified product, a multidosage container, a set for allergy treatment, to the method of treating and applying the specified product.

EFFECT: preparation of allergen as a high-soluble uncompacted dosage form which is high-soluble, stable and low-fragile enough.

99 cl, 25 tbl, 1 ex

 

This invention relates to a pharmaceutical product containing the allergen, and, in particular, to bestregistrycleaner solid dosage forms containing the allergen, and method of preparing such dosage forms.

The prior art inventions

Allergy is a significant health problem in countries where follow the Western way of life. In addition, in the above-mentioned countries, the prevalence of allergic diseases is increasing. Although allergies can not be regarded as a disease, life-threatening, asthma is the cause of a significant number of deaths each year. Exclusive distribution in approximately 30% of adolescents expressed a significant deterioration in the quality of life, loss of health and money and justifies the classification of allergies among the main health problems in the Western world.

Allergy is a complex disease. Many factors contribute to the process of sensitization. Among them, the susceptibility of the individual due to the still poorly understood interaction of several genes. Another important factor is the exposure to the allergen dose over certain thresholds. Some environmental factors may be important for the process of sensitization, including pollution, childhood infections is AI, parasitic infections, intestinal microorganisms, and so forth. Once an individual is sensitized and allergic immune response, the presence of extremely small quantities of the allergen effectively transformed into symptoms.

Natural course of allergic diseases is accompanied by a deterioration in two stages. First is the progression of symptoms and severity of the disease. For example, there is a progression from hay fever to asthma. Secondly, there is the dissemination of specific allergens that often leads to allergic multireactive. Chronic inflammation leads to a General weakening of the protective mechanisms of the mucosa, leading to nonspecific pain sensitivity and, ultimately, to the destruction of the mucosal tissue. Infants may develop hypersensitivity first to food, i.e. milk, resulting in eczema or gastrointestinal disorders; however, quite often referred to the symptoms they appear spontaneously. These babies are a group at increased risk of later in their lives inhalant allergies.

The most important sources of allergens found among the abundant particles of a certain size in the air we breathe. E and the sources are highly versatile and include grass pollen and mite excrement, living in household dust, which together are responsible for approximately 50% of all allergies. Also important is give animal dander, i.e. dandruff cats and dogs, other types of pollen, such as pollen of Artemisia, and microprobe, such as Alternaria. Depending on local conditions can dominate different types of pollen, such as birch pollen in Northern and Central Europe, ragweed in the Eastern and Central United States and pollen of Japanese cedar in Japan. Insects, i.e. bee and wasp venoms, and food products account for approximately 2% of all allergens, each separately.

Cause allergies, i.e. high sensitivity, is inappropriate immune response to foreign non-pathogenic substances. Important clinical manifestations of Allergy include asthma, hay fever, eczema, and gastrointestinal disturbances. Allergic reaction occurs and subsides within 20 minutes after contact with a specific allergen. In addition, the allergic reaction is specific in the sense that a specific individual sensitize specific allergen(s), while the individual does not occur necessarily an allergic reaction to other substances, which are known to cause allergic disease. Allergic phenotype is determined by sharply pronounced is the inflammation of the mucous membrane of the target organ and the presence of allergen specific antibodies of class IgE in the circulation and on the surface of mast cells and basophils.

Allergic attack is initiated by the reaction of alien with allergen allergen specific IgE-antibodies, when antibodies bind with high affinity IgE receptors on the surface of mast cells and basophils. Mast cells and basophils contain preformed mediators, i.e. histamine, tryptase and other substances, which are released when the cross-linking of two or more related receptor IgE antibodies. IgE antibodies are cross-linked as a result of simultaneous binding of one molecule of the allergen. Cross-stitching is associated with the IgE receptor on the surface of mast cells also leads to the release of the transmitting signal molecules responsible for the attraction of eosinophils, allergen specific T-cells and other cell types to the site of the allergic reaction. These cells when interacting with the allergen, IgE and effector cells lead to a renewed outbreak of symptoms that occur within 12-24 hours after the collision with the allergen (late phase reaction).

Elimination of allergic disease involves the recognition of the disease and treatment, including preventive activities. Diagnosis of Allergy is associated with detection of allergen specific IgE and identification of the source of the allergen. In most cases, a thorough history may be the residual for the establishment of allergies and to identify the source of specific allergen. However, most often the diagnosis is confirmed by objective research, such as injectable skin test/ blood test or provocative test.

therapeutic approach is based on three main categories of opportunities. The first opportunity is the elimination of the allergen or reduce impacts. In some cases, elimination of the allergen is evident, for example, in the case of food allergens in other Troubleshooting can be difficult or expensive, when it comes to feces of mites living in household dust, or it may be unenforceable as against pollen allergens. The second and most widely used therapeutic approach is to assign the classical symptomatic drugs like antihistamine drugs and steroids. Symptomatic medicines are safe and effective; however, they do not affect the natural cause of the disease and they do not inhibit the spread of the disease. The third therapeutic option is specific vaccination against Allergy, which in most cases reduces or alleviates symptoms of allergies caused by the allergen in question.

Common specific vaccination against Allergy is etiologic the tion therapy for allergic diseases. It interferes with the basic immune mechanisms leading to sustained improvement of the immune status of patients. Thus, in contrast to symptomatic drug therapy protective effect of vaccination against Allergy extends beyond the treatment period. Some patients receiving the treatment, cure, and the majority of patients experienced a weakening of the severity of the disease and symptoms, or at least, slow the progression of the disease. Thus, specific vaccination against Allergy has a protective effect, reducing the risk of turning hay fever to asthma and reducing the risk of development of new reactions of hypersensitivity.

Immune mechanism underlying successful vaccination against Allergy, in parts not installed. Specific immune response, such as the formation of antibodies against a particular pathogenic factor, known as the adaptive immune response. This response differs from the innate immune response, which is a nonspecific response against pathogenic factors. Vaccine Allergy focused on the adaptive immune response, which involves cells and molecules with antigenic specificity, such as T-cells, and producing antibodies b cells. B-cells are unable to Mature into cells that produce antibodies without the aid of the cells with the appropriate specificity. T cells that are involved in the stimulation of allergic immune responses are mainly cells of the Th2 type. I believe that establishing a new balance between Th1 cells and Th2 is favorable and the main immunological mechanism vaccination against Allergy. Is this with the reduction of Th2 cells, a shift from Th2 cells to Th1 cells or activation of Th1 cells is a controversial issue. In recent times suggest that regulatory T cells are important for the mechanism of vaccination against Allergy. In accordance with this model of regulatory T cells, i.e. cells Th3 or Tr1, inhibit both Th1 cells and Th2 cells with the appropriate antigenic specificity. Despite these ambiguities generally believe that active vaccine must possess the ability to stimulate allergen specific T-cells, preferably Thl-cells.

Despite its advantages, specific vaccination against Allergy is not widely adopted mainly for two reasons. One reason is the inconvenience associated with traditional vaccination program, which includes re-vaccination, such as injections over several months. Another reason, more important is the risk of allergic p. the adverse reactions. Regular vaccination against infectious pathogens effectively carried out using immunization with a single dose or multiple high doses. This strategy, however, cannot be used for vaccination against Allergy, since the pathological immune response is already a way of life.

Therefore, the conventional specific vaccination against Allergy is done using multiple subcutaneous immunization carried out over an extended period of time. The course is divided into two phases, phase of increasing doses and the stabilization phase. In the phase of increasing doses used increasing doses, usually during the 16-week period, starting with small doses. When you reach the recommended stabilizing dose, the dose used in the phase stabilization is usually in the form of injections every six weeks. After each injection the patient must remain under medical supervision for 30 minutes due to the risk of anaphylactic side effects, which in principle, although extremely rare, can be life-threatening. In addition, the clinic should be equipped to provide emergency treatment. There is no doubt that the vaccine is designed for a different way of introduction, will eliminate or reduce the risk of allergic side reactions of the common p is decornoy vaccine, and will also promote more widespread use may even allow the vaccination of the house.

Attempts to improve vaccine for vaccination against Allergy take for more than 30 years, and they include a variety of approaches. Some approaches focus on the allergen through the modification of the reactivity of IgE. Others focus on the method of administration.

Access to the immune system is possible through the oral cavity and mucous membranes of the oral cavity, for example, sublingual introduction of allergens is known by way of introduction.

Usually vaccinated against allergies with the use of the method of administration through the oral mucosa consists of periodic administration of certain doses of a solution of the allergen with intervals of length at least one day. For comparison, therapeutic (total) maintenance dose exceeds demand in comparable subcutaneous dose of 5-500 times. The obvious disadvantage of such dosage form and route of administration are the problems associated with accurate and uniform by the introduction of an accurate dose to the patient (may be assigned by a few drops, the homogeneity of the individual drops, the reliability of the application, and so forth). In addition, there is a need to cool the drug and to enable the drug to servanty.

Netien et al. ("Galenica 16 - Medicaments homeopathiques" ed. 2, 1986, p.77-99) describe a liquid solution, impregnated in the solid particles (granules)or pressed tablets of lactose, sucrose or mixtures thereof sublingual administration of drugs, such as allergen.

In DD-A.0107208 describe the cooking method conventional compressed tablets containing the allergen. With the introduction of the tablet dissolves in the saliva, and the allergen is then absorbed through the oral mucosa. The product contains water-insoluble filler, called talc, as well as paraffin and fatty acids, which are undesirable because they leave a bad taste in the mouth of the patient. In addition, the friction generated during the tabletting process, can be harmful to the physical stability of allergens.

In EP 278877 discuss pharmaceutical composition for sublingual application, in which the solid base is covered with a solution of the allergen when spraying the solution on the solid balls basis. Argue that the resulting preparation disintegrates quickly, but not instantly. However, not give any explanation as to reach the goal. In addition, the product contains reducing sugar in the form of lactose, which tend to interact with allergens.

In order to ensure that as much of the input dose defined by the CSO allergen, as possible, is present on the mucous membrane of the oral cavity and that, furthermore, the contact time of the disintegrated product from the mucous membrane is maximized, it is very important that the dosage form getintegervalue would instantly upon contact with the saliva of the oral cavity. Bistrotdepierrerue solid dosage forms, which rapidly release the active ingredient into the oral cavity, known in this field.

In U.S. patent No. 4371516 are pharmaceutical dosage forms containing the active ingredients, which rapidly disintegrate in water. Pharmaceutical dosage forms contain uncoated matrix grid of material media, which disintegrates within 10 seconds.

Media-based dried by freezing fish gelatin, which is described in WO 00/61117 designed to instantly release of the active ingredient upon contact with saliva when introduced into the oral cavity.

Media from dried by freezing modified starch, which is described in WO 00/44351, designed for instant release of the active ingredient upon contact with saliva when introduced into the oral cavity.

In WO 99/21579 describe bistrotdepierrerue dosage form, containing vaccine and adjuvant for oral administration.

In WO 02/13858 are fast the dissolving pharmaceutical composition, containing vaccines in the form of a rapidly dissolving "cakes" for oral administration. Was that the purpose of the WO 02/13858 is to provide viral and bacterial vaccines, which will remain intact in the gastrointestinal tract. This is achieved by protection of the antigen from the acidic stomach contents introduction the cake antacids such as calcium carbonate.

In WO 00/51568 describe bystrodeistviyu pressed tablet with low fragility, which is intended to dissolve in the mouth upon contact with saliva in less than 30 seconds with the formation of "easy to swallow" suspension.

In U.S. patent No. 4371516 argue that the drug is useful for oral vaccines. In the case of patents WO 00/61117, WO 00/44351, WO 99/21579 and WO 02/13858 also argue that the invention is aimed at non-communicable immunomodulating condition, such as systemic allergic conditions, such as hay fever. However, there is no description in any of the above messages for technical information or examples of how you can make bistrotdepierrerue solid vaccine dosage form, containing the allergen. For example, there is no guidance on the appropriate dosage of a particular allergen in any of the above drugs. It is very important to enter the exact dose of allergen, the patient is at, as an excessive dose may cause anaphylactic shock in a patient. Also, do not give any description of the relevant criteria or guidance on such criteria in terms of stability or fragility of such drugs.

Summary of invention

This invention relates to a pharmaceutical product suitable for the introduction of the allergen through the mucous membrane of the oral cavity containing at least one allergen and the matrix, in the form of bistrotdepierrerue solid dosage form, characterized in that contains the allergen dosage form is stable, strong enough and does not release dangerous quantities of allergen residues when used by the patient.

In addition, bistrotdepierrerue non-compacted solid dosage form suitable for insertion through the mucous membrane of the oral cavity contains a substance called the matrix, and the allergen, in which the allergen is stable, and the dosage form has a low fragility with regard to the release of the allergen, dosage form dissolves quickly and does not require the presence of adjuvant.

In particular, the invention relates to a pharmaceutical product, which is suitable for injection of allergen containing:

bistrotdepierrerue non-compacted solid dosage form suitable for in which edenia through the oral mucosa, which contains:

(a) a matrix formed by at least one forming the matrix substance, and

(b) an effective dose of the allergen to desensitization of the individual in relation to these allergen, in which

(c) loss of the content of the allergen in the said dosage form is less than 50% of the initial content of allergen after storage for 3 months at 25°C and 60% relative humidity, and

(d) loss of the allergen from the named solid dosage form is approximately less than 0.5 micrograms of allergen extract or approximately less than 0.05 μg of the main allergen in the test fragility.

In one preferred embodiment of the invention, the solid dosage form contains fish gelatin and mannitol as substances forming the matrix.

In another preferred embodiment of the invention, the solid dosage form contains starch and mannitol as substances forming the matrix.

In the present invention are also methods of obtaining the considered solid dosage forms and methods of treating allergies by introducing the aforementioned solid dosage forms.

Detailed description of the invention

This invention is based on the number of surprising results, none of which the source could not have reasonably expected. First, it is based on in the water, that it is possible to apply bistrotdepierrerue non-compacted dosage form for administration of an allergen and what is possible to achieve effective treatment of allergies as a result of application of this preparation. In particular, it is shown that it is indeed possible to deliver a sufficient amount of allergen in the immune system of the patient through the mucous membrane of the oral cavity using bistrotdepierrerue non-compacted solid dosage form, without causing undesirable level of side effects. In addition, in this invention include the appropriate dose levels for a therapeutic effect without unacceptable side effects.

Secondly, the invention is based on the data that effective treatment can be achieved using bistrotdepierrerue non-compacted dosage form without the use of adjuvant.

Thirdly, the invention is based on the data that it is possible the preparation of allergen in the form of bistrotdepierrerue non-compacted dosage form, although allergen requires special conditions for its stability and low brittleness. In particular, it is shown that it is possible to balance the different requirements to dosage form, on the one hand, was bistrotdepierrerue and, on the other side is us, both stable and was characterized by low fragility in order to obtain a dosage form, which is sufficiently bistrotdepierrerue, stable and has a low fragility.

Allergenic proteins are susceptible to degradation, which is influenced by a number of environmental factors, where they meet. Argue that this is related to the treatment of allergies and, in particular, vaccination against Allergy to the allergen is delivered intact to the immune system in therapeutically relevant doses. So, the allergen must remain stable during production, storage and application. In this paper shows that it is indeed possible to introduce allergenic proteins in the composition bistrotdepierrerue non-compacted dosage form, which is stable in respect of doses of the allergen and activity of the allergen. In addition, it has been unexpectedly found that describes the drugs really stable at room temperature. This result has significant implications for the ways of processing the final product. Cooling production equipment during transport or during storage in a pharmacy is often associated with high cost, because the cooling equipment must be carefully controlled, and investing money in a reliable cooling equipment to provide the correspondingly very expensive. In addition, for the convenience of the patients also preferably, dosage form can be stored at room temperature.

Thus, in this paper it is shown that it is indeed possible to introduce allergenic proteins in the composition bistrotdepierrerue non-compacted form of drug that is therapeutically effective, without the need for Freund. These contain the allergen solid dosage forms, in addition, is stable under favorable conditions.

When allergenic proteins produced in the form of bistrotdepierrerue non-compacted dosage form, the advantage is the fact that the resulting dosage form essentially does not release the allergens in the environment or on the subject, touching the dosage form, by direct contact. Previous non-compacted bistrotdepierrerue solid dosage forms was characterized by a low mechanical strength compared to compressed tablets, due to the nature of the non-compacted matrix, which is fragile and brittle, almost like a wafer. During, for example, packaging, storage, transportation dosage forms and manipulations with her patient remaining particles containing the allergen, can be released into the environment and the patient. It is particularly dangerous is that when the active ingredient is an allergen, so as allergen can cause an allergic reaction in manipulating the subject or to induce an allergic reaction, such as sensitization, or allergic response, depending on the dose. Suppose that the maximum permissible levels of environmental pollution in the form of, for example, the allergen in dust depend on the considered allergen and should take up to 2 micrograms of the main allergen per gram of house dust (Allergy. Principles and practice (1993, 4th ed.), Mosby-Year book. Vol.I, str).

Non-compacted bistrotdepierrerue dosage form, which is obtained by removing the liquid from solidifying system containing substances forming the matrix, the active ingredient and other possible substances, preferably produced in situ. Method for the production of in situ mostly involves removal of the solvent from the solidified system consisting of the active ingredient and forming a matrix of excipients in the final container, such as blister packaging. The in situ method, used for commercial purposes, does not provide for the common coating of the dosage form. The coating of the dosage form in most cases can influence the dispersion of solid dosage forms, thus compromising the properties of the medicament the military form of instant release.

Therefore, despite the opposite nature of the above-mentioned requirements, in this paper it is shown that it is indeed possible to prepare an effective dosage of allergenic proteins in bistrotdepierrerue non-compacted dosage form, while achieving at the same time, low brittleness and maintaining the ability to quickly dispersing.

All of the above results are confirmed by experimental laboratory work or preclinical experiments using experimental animals, when it is required or clinical trials if necessary.

The term "bistrotdepierrerue dosage form" refers to dosage forms that disintegrate approximately less than 90 seconds, preferably approximately less than 60 seconds, preferably in less than 30 seconds, more preferably less than 20, even more preferably approximately less than 10 seconds in the mouth, even more preferably less than 5 seconds, and most preferably approximately less than 2 seconds after introduction into the oral cavity. Solid dosage form of the invention may be in the form of tablets, capsules, pellets or tablets in the form of a capsule.

The term "non-compacted" refers to a solid dosage form, which is prepared by removing the liquid issaturday system, containing substances forming the matrix, the active ingredient and other suitable ingredients, getting the result contains the allergen solid matrix.

The term "solid dosage form" refers to the standard dosage form, which is not a liquid or powder when introduced into the oral cavity, thus, the term "solid dosage form" refers, for example, tablets containing the standard dose of the active ingredient.

The terms "tablet", "hard drug and vaccine form" are used interchangeably.

The term "substance, which forms the matrix" refers to any pharmaceutically suitable water-soluble or dispersible in water filler, which will serve as a carrier for the active ingredient in a solid dosage form.

The term "filler" refers to any component that can be added to the drug, in addition to the active ingredient.

The term "loss of the content of the allergen in the said dosage form" refers, for example, degradation or inactivation of the allergen in the dosage form during, for example, storage, transportation and application. The loss can be set or as a loss in biological activity/efficiency, or how the loss of the actual content of the allergen. predpochtitelno, the loss of the content of the allergen is defined as the loss of at least one of the main allergen. Loss, for example, can be estimated using the ELISA method described Obispo et al. (Allergy, 1997, 52, str-813), using the allergen-specific reagents.

The term "loss of the allergen content of the above-mentioned dosage form" refers, for example, the release of the allergen in the dosage form during, for example, storage, transportation and application. The loss can be set or as a loss in biological activity/efficiency, or how the loss of the actual content of the allergen. Preferably, contents loss allergen is defined as the loss of at least one of the main allergen. Loss, for example, can be estimated using the ELISA method described Obispo et al. (Allergy, 1997, 52, str-813), using the allergen-specific reagents.

The term "stable" refers to dosage forms in which the reduction in the allergen content is less than 50% of the initial content after storage for 3 months at 25°C and 60% relative humidity in the final container or have reduced biological activity/efficiency, or as a loss in the content of the at least one primary allergen. Loss, for example, can be assessed using ELISA method, as described above.

The term "low is I brittleness" refers to the number allergiesallergies material, which is lost from the dosage form when exposed to an external force. Solid dosage form has sufficient fragility and strength, so that it can be transported, stored and shift, if the lost material containing the allergen, contains less than 0.5 micrograms of allergen extract or 0.05 μg of the main allergen in solid dosage form. For purposes of this invention, the fragility can be estimated by the method according to this invention.

"Tensile strength 5" calculated according to the following equation:

δ=3Wa×9,nm-2/2d2b

where W is the maximum load at break (kgf),

a - the distance between the carriers,

d is the thickness bistrotdepierrerue solid dosage forms (mm)

b - diameter bistrotdepierrerue solid dosage forms (mm).

"Maximum load at break" means the maximum force required to rupture the entire form when tested in three-point bending using an appropriate tool (for example, ST5, Engineering Systems, I Loach Court, Radford Bridge Road, Nottingham NG8 1NA, UK).

The expression "introduction through the mucous membrane of the oral cavity" refers to a way of introduction, in which the dosage form is placed under the tongue or elsewhere in the oral cavity, allowing the active ingredient to contact with oral mucosa or g is otci patient to achieve local or systemic action of the active ingredient. An example of the method of administration through the oral mucosa is sublingual administration.

The expression "sublingual introduction" means the method of introduction, in which the dosage form is placed under the tongue to achieve local or systemic action of the active ingredient.

The term "allergen" refers to any naturally occurring protein or mixture of proteins, which, as described, induce allergic, that is IgE mediated, reactions when re-exposed to the individual. Examples of naturally occurring allergens include pollen allergens (allergens pollen tree, weed, herbs, and grasses), tick-borne allergens (e.g., mites that live in house dust and mites living in the repository), insecticidal allergens (volatile and originating from saliva and venom allergens), animal allergens from, for example, saliva, hair and dandruff, for example, dogs, cats, horses, rats, mice, and so forth, fungal allergens and food allergens. Allergens can be used in the form of the allergen extract, a purified allergen, a modified allergen, or recombinant allergen, or recombinant mutant allergen, any fragment of an allergen, contains more than 30 amino acids, or any combinations thereof.

Used in the description, the expression "extract allergen" memotrie to extract obtained by extraction of the biological material source of the allergen, as basically described in "Allergenic extracts", H.Ipsen et al., chapter 20 in Allergy, principle and practise (Ed. S.Manning) 1993, Mosby-Year Book, St. Louis. This extract can be obtained by water extraction of the water-soluble material with subsequent purification stages, such filtration to obtain a solution, i.e. the extract. Then the extract can be subjected to further purification and/or processing, such as drying, freezing, which removes essentially all the water. In General, the allergen extract contains a mixture of proteins and other molecules. Allergenic proteins are often classified as a major allergen, intermediate allergen, a minor allergen or unclassifiable. The allergen extract typically contains both the main and minor allergens. The main allergens are usually about 5-15% of the average of the extract of the allergen, usually about 10%. Classification of allergens based on the evaluation of the clinical significance of individual allergen and are presented below. Examples of important major allergen found in the extract include allergens of grass group 1 and 5 and 6 (for example. Phi p 1, 5 and 6), allergens group dust mites 1 and 2 (e.g., Der p 1, Der p 2), pollen allergen tree 1 (Bet v 1), allergen cedar pollen 1 and 2 (for example. Cry j 1, Cry j 2), pollen allergen of ragweed 1 and 2 (Amb a 1, Amb a 2), Kosh is a food allergen 1 (Fel d 1). The average allergic subject can sencibilisiruet one or more major allergens and to respond to one or more of the major allergens, and in the future may also sencibilisiruet minor allergens and to respond to them.

The amount of allergen extract mentioned in the description, refer to the dry matter content of such extracts of the allergen.

Preferably, the water content of dry matter is less than 10%, more preferably 5% by weight.

Used in the description, the expression "biological material source of the allergen" refers to any biological material containing one or more allergens. Examples of such materials are tick RMV (clean torso mite) or WMC (culture of the whole mite), defatted or not defatted pollen, for example, herbs, plants, weeds and trees, hair and animal dander, skin, mycelium and spores of fungi, body, poison, or saliva of insects and food.

Biological materials the source of the allergen may contain polluting materials, such as alien pollen and fragments of plants and flowers on the material source of allergenic pollen.

The degree of contamination should be minimised. Preferably, the content of impurities should not exceed 10% (wt./wt.) mass of biological material source.

Usually the former is ract allergen contains, at least 10% of the protein content of dry matter of the extract of the allergen, which is determined by the standard method for protein research, such as ICA or Lowry method, and the remainder consists of other "non-protein material, which may represent components such as lipids, hydrocarbons or bound water, which come from a biological source of the allergen.

The extract of the allergen can be prepared and stored as dried by freezing the material, obtained by drying by freezing the liquid extract of the allergen at a pressure below 800 microbar and during the period up to 100 hours with removal of water.

In extracts of the allergens there is no internationally recognized method of standardization. There are a number of units of activity of the extract, i.e. the bioactivity. The applicable methods and units are usually used to assess the allergen content and biological activity. Examples of this are SQ-units (standardized unit of quality), BAU (biological units allergen), BU (biological unit), UM (unit of mass), IU (international units) and IR (index of reactivity). Therefore, if used extracts of sources beyond those considered in the description, they need to standardize with respect to the given description extra is that for in order to determine its activity in units SQ or any of the above-mentioned units. The subject matter considered in Allergenic extracts", H.Ipsen et al., chapter 20 in Allergy, principle and practise (Ed. S. Manning 1993, Mosby-Year Book, St. Louis and Lowenstein, H. (1980) Arb Paul Ehrlich Inst 75:122.

The bioactivity, i.e. allergenic activity in vivo, this extract depends on a number of factors, the most important factor is the content of major allergen in the extract, which varies depending on the composition of the biological material source.

The amount of allergen extract in grams, which should be used to obtain the desired bioactivity, varies depending on the type of the examined extract, and for this type of extract the number of allergen extract changes from one party to another depending on the actual bioactivity of the extract.

For this batch extract the number of allergen extract in grams, which should be used to obtain the desired bioactivity, can be set using the following procedure:

a) the Bioactivity of various control quantities of the extract is determined using one or more immune in vivo tests to establish the relationship between the bioactivity and the number of control extract. Examples called immune in vivo tests are injectable skin test (SPT), end of chivalry provocative test (CPT) bronchial provocative test allergen (ICA) and various clinical tests which monitor one or more symptoms of allergies, see, for example, Haugaard et al., J Allergy Clin Immunol, Vol.91, No 3, pp. 709-722, March 1993.

b) On the basis of the established relationship between bioactivity and the number of control extract the biological activity of one or more of the appropriate doses for use in the dosage forms of the invention chosen with due consideration of the balance of factors: i) the treatment or relief of symptoms of allergies, ii) side effects registered in immune tests in vivo, and (iii) variability of (i) and (ii) from one individual to another. Balance the factors to get the most adequate therapeutic effect without taking an unacceptable level of side effects. The method of equilibrium factors well known to specialists in this field.

The biological activity of one or more installed the appropriate doses can be expressed in any suitable units of bioactivity, such as units SQ, BAU, IR and IU, compare above.

c) On the basis of the control extract prepare one or more bioactive control standard extracts and, if used, size of units of bioactivity control standard extracts calculated on the basis of the quantities of units bioa the activity, designed for one or more of the appropriate doses, for example, the standard for BAU can be obtained from the FDA that illustrate below.

O.) On the basis of the control standard extracts of each type of extract you choose the number of parameters to assess the bioactivity of the extracts. Examples of such estimated parameters are common allergenic activity, the number of installed main allergens and complete molecular composition of the extract. Full allergenic activity can be assessed using a competitive immunoassay in vitro, such as ELISA and immunofluorescent analysis MagicLite® (LIA) with the use of a standardized mixture of antibodies raised against the extract obtained using standard methods, for example, antibodies grown in mouse or rabbit, or a pool serum of allergic patients. The content of major allergen can, for example, quantified using rocket immunoelectrophoresis (RIE) and compared with the control standards. The complete molecular composition can be investigated using, for example, cross-immunoelectrophoresis (CIE) and polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate (SDS-PAGE).

e) with regard to the party of the extract with an unknown bioactivity (test extract), the amount of extract that should be used is owano to obtain the desired level of bioactivity (effective dose for use in the solid dosage form according to this invention), you can install as follows: for each selected performance parameter of the tested extract compared with the control standard extracts, using appropriate methods of measurement, which are described above, and on the basis of the measurement results calculate the quantity of extract with the desired bioactivity.

SQ-unit: SQ-unit is determined in accordance with the method of standardization "SQ-bioactivity" ALK-Abello A/S, which 100000 SQ is equivalent to standard subcutaneous maintenance dose. Typically, 1 mg of the extract contains from 100000 to 1000000 units SQ depending on the source of allergens from which they originate, and used production method. The exact amount of the allergen can be installed using immunoassay, i.e. the total content of major allergens and total allergenic activity.

BAU (units of biological allergen) is a unit of biological activity, which is determined in accordance with the requirements of the FDA for allergenic product, described in "Quantitative determination of relative potency of allergenic extracts" ("Methods of the allergen products testing Laboratory" "ELISA competition assay". P. 15, #49N-0012, FDA, October 1993). Dose of 100000 SQ contained in the herbal extract in line with the 2600-4700 BAD according to the above method. Similarly, other extracts can be estimated in accordance with privedennym way.

The expression "effective dose allergen for desensitization" will mean dose, which, when used once or repeatedly in the monodose or with increasing doses, leads to, for example, the adaptive immune response and, thus, serves as a means for hyposensitization allergic patients. Preferably, the expression must mean the amount of allergen in each dosage form required in order to induce an adaptive immune response after repeated introduction of the named solid dosage forms in accordance with the scheme of treatment (during the period ranging from several applications to at least one daily use for several months). Preferably, desensitization involves relieving symptoms of allergies with a dose. Clinical Allergy symptoms include rhinitis, conjunctivitis, asthma, urticaria, eczema, covering reactions to the skin, eyes, nose, upper and lower respiratory tract, with common symptoms such as redness and itching of the eyes and nose, itching, and runny nose associated with a nagging pain, difficulty breathing, shortness of breath, itching and swelling of tissue.

Used in the description, the expression "content uniformity" refers to the variability of doses of the prescribed dose.

Used the phrase "sod the neigh water" refers to the content of the remaining water in standard solid medicinal dosage form, which is quantitatively determined using a titration Karl Fischer. Named method is based on the principle that this number Is leads to the transformation of an equivalent amount of water (European Pharmacopoeia (EP), 3rd edition, 2.5.12).

Used the term "water activity aw" refers to the existing water in the sample. Measuring water activity carried out using methods known to experts in this field, for example, by determining the point of condensation on the surface of the chilled mirror, using detectors relative humidity, which changes the electrical resistance or capacitance, or by using an electrode with lithium chloride:

awyou can count on in accordance with the following equation:

aw=p/ps=ERH(%)/100

where

p - partial pressure of water vapor on the surface of the product

ps is the saturation pressure or partial pressure of water vapor around pure water at the product temperature,

ERH - equilibrium relative humidity.

The term "about" or "approximately" means within an appropriate range for a certain value set by any person skilled in the art, which will depend in part on how the value is measured or determined, for example, from the limitations of the measurement system. In the example, "about" can mean a range of up to 20%, preferably up to 10%, more preferably up to 5% and even more preferably up to 1% of this value.

Currently, it is shown that the solid dosage form according to the invention is a pharmaceutical allergenic product, administered through the oral mucosa, which provides an effective dose of the allergen causing the allergen-specific immune response depending on the dose and exhibiting acceptable side effects.

In addition, we discovered that it's really possible to produce non-compacted bistrotdepierrerue solid dosage form with low fragility allergen, which is strong enough and does not release harmful amounts of residue after use by the patient.

In addition, it was found that these medications were stable at room temperature.

Allergens in varying degrees, are particularly susceptible to degradation in the aquatic environment, such as an aqueous solution of the allergen, or in a product with a high content of water and/or high activity in the water.

In the monograph of the European Pharmacopoeia concerning food allergens and in the "Note for guidance on allergen products, CPMP (London, 13 March 1996) claim that the moisture levels should not exceed 5% for dried by freezing products(i.e allergen extracts in capsules), and the products should be stored frozen (-20°C). Store refrigerated (2-8°C) is also a requirement for liquid sublingual drugs, which, in addition, have a limited shelf life. Found that allergens, including unstable allergens, stable in room temperature conditions. Even a dosage form according to the invention, having a water content above the prescribed maximum level of 5%, stable at room temperature. Without referring to theory, this fact can be explained by the fact that the fillers bistrotdepierrerue solid dosage forms bind the remaining water in the dosage form and reduce the water activity of solid dosage forms containing the allergen. Therefore, by reducing the water activity of the drug, it is possible to obtain a stable drug without degradation of the allergen, even if the water content is higher than the maximum level of 5%, which is set for allergen extracts in capsules.

Water activity is an important factor contributing to the storage of the product. It is well known that the water activity of the product affects the growth of bacteria, as well as on the stability, efficiency and consistency of a pharmaceutical product. Also on the stability of the protein has a significant influence of water activity, SLE is due to the relatively fragile nature of proteins. Most proteins must maintain conformation to save the activity. Maintaining low levels of water activity helps to prevent conformational changes or to contribute to the conformational changes that subsequently prove important to ensure that the protein in the form of allergen stable. Also on the hydrolytic degradation of proteins, or caused by enzymes or not, affects the activity in the water.

In addition, suppose that the water content will affect the mechanical strength of solid dosage forms. In General, high values will increase the risk that the solid dosage form will become more liquefied, while a lower value will affect the strength of solid dosage forms, for example, solid dosage form will become more fragile and brittle.

Measuring water activity carried out using methods known to experts in this field, for example, by determining the point of condensation on the surface of the chilled mirror, using detectors relative humidity, which changes the electrical resistance or capacitance, or by using an electrode with lithium chloride.

Water activity of solid dosage forms preferably does not exceed 0,70 and is preferably from 0.1 to 0.7, more is predpochtitelno is from 0.2 to 0.6, more preferably from 0.3 to 0.5, and most preferably ranges from 0.4 to 0.5.

The water content of a solid dosage form is determined according to the method described in example 1, preferably not more than 25% and preferably 0.1-20%, more preferably is from 0.5 to 15%, more preferably is 2 to 8%, more preferably is 4-7%, most preferably ranges from 4.5 to 6% water.

According to one embodiment of the invention allergenic pharmaceutical product provide in the form bistrotdepierrerue solid dosage form that dissolves quickly in the oral cavity upon contact with saliva, thus, leading allergen in close contact with the relevant immune tissue, mucous membrane, and allowing the allergen to go to it. Examples of naturally occurring allergens include pollen allergens (allergens pollen of trees, plants, weeds, and grass), insect allergens (volatile allergens, allergens saliva and venom, for example, allergens mites, cockroach allergens, and small two-winged insects, allergens in Hymenoptera venom), allergens hair and dandruff animals (e.g. dogs, cats, horses, rats, mice and so on) and food allergens. Important pollen allergens of trees, herbs and plants are allergens that occur on the taxonomic units Fagales, Oleales, Finales and Platanaceae including, for example, birch (Betula), alder (Ainus), hazel (Corylus), hornbeam (Carpinus) and olive (Olea), cedar (Cryptomena and juniperus), plane tree (Platanus), the detachment of Poales including, for example, a grass of the genus Lolium, Phleum, Poa, Cynodon, Dactylis, Holcus, Phalaris, Secale, and Sorghum, units Asterales and Urtlcales, including, for example, plants of the genus Ambrosia, Artemisia, and Parietaria. Other important inhaled allergens are allergens mites that live in household dust, of the genus Dermatophagoides and Euroglyphus, storage mites, for example, Lepidoglyphys, Glycyphagus and Tyrophagus, allergens, cockroaches, small dipteran insects and fleas, for example, Blatella, Periplaneta, Chironomus and Ctenocepphalides, and allergens mammals such as the cat (genus Felis), dog (genus Canis), cow (genus Bos) and the horse (genus Equus), allergens, poisons, including allergens originating from burning and stinging insects, such as representatives of the taxonomy of the order Hymenoptera, including bees (superfamily Apidae), wasps (superfamily Vespidea) and ants (superfamily Formicoidae). Important inhaled allergens fungi are, for example, allergens originating from the genus Alternaria and Cladosporium.

In a more preferred embodiment of the invention allergens are Bet v 1, AlN g 1, Cor a 1 and Car b 1, Que a 1, Cry j 1, Cry j 2, Cup a 1, Cup s 1, Jun a 1, Jun a 2, jun a 3, Ole e 1, Lig v 1, Pla-1 Pla a 2, Amb a 1, Amb a 2, Amb t 5, Art v 1, Art v 2, Par j 1, Par j 2, Par j 3, Sal k 1, Ave e 1, Cyn d 1, Cyn d 7, Dac g 1, Fes p 1, Hol I 1, Lol p 1 and 5, Pha a 1, Pas n 1, Phl p 1, Phl p 5, Phl p 6, Poa p 1, Poa p 5, Sec 1, Sec 5, Sor h 1, Der f 1, Der f 2, Der p 1, Der p 2, Der p 7, Der 1. Eur m 2, Gly d 1, Lep d 2, Blo t 1, Tyr p 2, Bla g 1, Bla g 2. Per a 1, Fel d 1, Can f 1, Can f 2, Bos d 2, Equ 1, Equ C 1. Equ 3, Mus m 1, Rat n 1, Apis m 1, Api m 2, Ves v 1, Ves v 2. Ves v 5, Dol m 1, Dol m 2, Dol m 5, Pol a 1, Pol a 2, Pol a 5, Sol 1, Sol i 2, Sol i 3 and Sol I 4, Alt a 1, Cla h 1, Asp f 1. Bos d 4, Mal d 1, Gly m 1, Gly m 2, Gly m 3, Ara h 1, Ara h 2. Ara h 3, Ara h 4, Ara h 5, or mixed hybrids of any of the listed allergens from Molecular Breeding (Maxygen, Inc.).

In the most preferred embodiment of the invention the allergen is an allergen is grass pollen or mite allergen living in dust, or ragweed allergen or allergen cedar pollen or cat allergen, or birch allergen.

In yet another embodiment of the invention bistrotdepierrerue solid dosage form contains at least two different types of allergens, or originating from the same source of allergens, or originating from different sources of allergens. For example, bistrotdepierrerue solid dosage form contains allergens of grass group 1, herbal group 2/3 grass group 5 and herbal groups 6 and tick-borne allergens group 1 and group 2 different tick species and grasses, respectively, allergens weeds, such allergens low and giant ragweed allergens various fungi like Alternaria and Cladosporium, allergens trees, such as allergens of birch, hazel, hornbeam, oak and alder, food allergens, such as allergens peanuts, soy and milk is.

Allergen included in bistrotdepierrerue solid dosage form may be in the form of an extract, a purified allergen, a modified allergen, a recombinant allergen or a mutant of a recombinant allergen. The extract of the allergen, by nature, can contain one or more isoforms of the same allergen, whereas recombinant allergen is usually only one of the isoforms of the allergen. In a preferred aspect, the allergen is an extract. In another preferred embodiment the allergen is a recombinant allergen. In the following preferred embodiment the allergen is found in nature in small IgE-binding mutant or recombinant small IgE-binding mutant.

Allergens may be present in equimolar amounts, or the present value of allergens preferably can be changed up to 1:20.

In the following embodiment of the invention a small IgE-binding allergen is an allergen according to WO 99/47680, or WO 02/40676, or PCT/DK 03/00322 ("Allergen mutants").

There are several laboratory methods for the characterization of the allergen. The most widely used methods are the polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate (SDS-PAGE), isoelectric focusing (IEF), cross immunoelectrophoresis (CIE) and rocket immunoelectrophoresis (RIE). Quantitative determination of individual allergens can be performed using a number of methods of quantitative immunoelectrophoresis (QIE), radial immunodiffusion (RIE) or enzyme-linked immunosorbent assay (ELISA). Determination of total allergenic activity most often carried out using radioallergosorbent test (RAST), analysis of Magic Lite (LIA) or related methods. You can also use the methods based on ELISA analysis.

The guide is usually applied suitable methods of determining the bioactivity include, for example, in the Note for Guidance on Allergen Product; The European Agency for the Evaluation of Medicinal Product, CPMP_BWP_243_96, London, 1996.

Classification as a major allergen allergen can be some of the tests. The allergen is usually classified as a major allergen, if at least 25% of patients demonstrate a strong IgE-binding (figure 3) and at least moderate binding (figure 2) from 50% of patients, the binding is determined using a screaming man (cross radioimmunoelectrophoresis). (Strong binding when a screaming man, that is, the visible IgE-binding to x-ray film in a day; moderate binding when a screaming man, that is binding after 3 days; weak binding when a screaming man, that is binding in 10 days). With strong IgE-binding, at least 10% of patients allergen classified as intermediate the first allergen, and undoubtedly the specific binding at less than 10% of patients allergen is classified as a minor allergen. Other methods can also be used to determine the binding of IgE, for example, IgE blot.

When classic with increasing dose desensitization, in which the dose of allergen in the form of bistrotdepierrerue solid dosage form is increased to a certain maximum, preferred activity standard dose dosage form is 150-1000000 SQ-units/dosage form, more preferred activity is 500-500000 SQ-units/dosage form, more preferred activity is 500-375000 SQ-units/dosage form, more preferred activity is 2500-375000 SQ-units/dosage form, more preferred activity is 2500-250000 SQ-units/dosage form, more preferred activity is 25000-250000 SQ-units/dosage form, more preferably 25000-125000 SQ-units/dosage form, more preferably 25000-100000 SQ-unit/medical form and the most preferred activity is 25000-75000 SQ-units/dosage form.

In another embodiment of the invention, the solid dosage form is repeatedly input monodose, preferably in the range of 2500-375000 SQ-units/dosage form, more preferably 2500-250000 SQ-units/l of the drug form more preferably 25000-250000 SQ-units/dosage form, more preferably 25000-125000 SQ-units/dosage form, more preferably 25000-100000 SQ-units/dosage form, and most preferably 25000-75000 SQ-units/dosage form.

In a particularly preferred embodiment of the solid dosage form contains the herbal extract of the allergen, in which the activity is 150-1000000 SQ-units/dosage form, more preferred activity is 500-500000 SQ-units/dosage form, more preferred activity is 500-375000 SQ-units/dosage form, more preferred activity is 2500-375000 SQ-units/dosage form, more preferred activity is 2500-250000 SQ-units/dosage form, more preferred activity is 25000-250000 SQ-units/dosage form, more preferred activity is 25000-125000 SQ-units/dosage form, more preferred activity is 25000-100000 SQ-unit/medical form and the most preferred activity is 25000-75000 SQ-units/dosage form.

In another embodiment the activity of the solid dosage form according to the invention is approximately 5-50000 BAU/dosage form, more preferred activity is 15-25000 BAU/dosage form, more preferably the activity which constitutes approximately 15-17600 BAU/dosage form, more preferably the activity is approximately 65-17600 BAU/dosage form, more preferably the activity is approximately 65-15000 BAU/dosage form, more preferably the activity is approximately 650-15000 BAU/dosage form, more preferred activity is 650-6000 BAU/dosage form, more preferred activity is 650-4700 BAU/dosage form, and the most preferred activity is 650-3500 BAU/dosage form.

In another embodiment of the invention, the solid dosage form is repeatedly input monodose preferably in the range of approximately 65-17600 BAU/dosage form, more preferably approximately 65-15000 BAU/dosage form, more preferably approximately 650-15000 BAU/dosage form, more preferably 650-6000 BAU/dosage form, even more preferably 650-4700 BAU/dosage form, most preferably 650-3500 BAU/dosage form.

In a particularly preferred embodiment of the solid dosage form contains the herbal extract of the allergen, the activity of which is approximately 5-50000 BAU/dosage form, more preferably the activity is 15-25000 BAU/dosage form, more preferably the activity is closer the Ino 15-17600 BAU/dosage form, more preferably the activity is approximately 65-17600 BAU/dosage form, more preferably the activity is approximately 65-15000 BAU/dosage form, more preferably the activity is approximately 650-15000 BAU/dosage form, more preferably 650-6000 BAU/dosage form, more preferably 650-4700 BAU/dosage form, most preferably 650-3500 BAU/dosage form.

Typically, 1 mg of allergen extract contains from 100000 to 1000000 SQ-units. This means that 1000000 SQ contained in 1 mg of the extract to 10 mg of the extract of the allergen and that 100000 SQ contains 0.1 mg of extract to 1 mg of the extract of the allergen. Similarly, any SQ-dose can translate into a range of doses of the allergen extract. On this basis, the above dose ranges presented in SQ can be counted in the ranges of doses in mg or μg of the extract of the allergen, and for the lower limit of the SQ range, use the lower limit of the appropriate range of the extract of the allergen, and the upper limit of the SQ range using the upper limit of the appropriate range of allergen extract.

Thus, in this embodiment the solid dosage form according to the invention has a content of the extract of the allergen approximately 0.15 μg - 10 mg/dosage form, more predpochtitel what about the content of the extract of the allergen is approximately 0.5 μg - 5 mg/dosage form, more preferably the content of the extract of the allergen approximately 0.5 mg 3.75 mg/dosage form, more preferably the content of the extract of the allergen approximately 2.5 mg 3.75 mg/dosage form, more preferably the content of the extract of the allergen approximately 2.5 μg to 2.5 mg/dosage form, more preferably the content of the allergen extract about 25 μg to 2.5 mg/dosage form, more preferably about 25 mg - 1.25 mg/dosage form, more preferably about 25 μg - 1 mg/dosage form, most preferably about 25 mg to 0.75 mg/dosage form.

In another embodiment of the invention, the solid dosage form is repeatedly input monodose preferably within a range of approximately 2.5 mg 3.75 mg/dosage, more preferably 2.5 mg to 2.5 mg/dosage form, more preferably about 25 μg to 2.5 mg/dosage form, more preferably about 1.5 mg - 1.25 mg/dosage form, more preferably about 25 μg - 1 mg/dosage form, most preferably about 25 mg to 0.75 mg/dosage form.

In the next incarnation in the solid dosage form according to the invention the content of the core the main allergen is approximately 0,015 mg - 1 mg/dosage form, more preferably about 0.05 μg - 500 μg/dosage form, more preferably about 0.05 mg to 375 mg/dosage form, more preferably about 0.25 microgram - 375 μg/dosage form, more preferably approximately 0.25 μg - 250 μg/dosage form, more preferably about 2.5 μg - 250 μg/dosage form, more preferably of 2.5 ug - 125 μg/dosage form, more preferably about 2.5 μg - 100 μg/dosage form, most preferably about 2.5 μg - 75 μg/drug form.

In another embodiment of the invention, the solid dosage form is repeatedly input monodose preferably within the range of 0.25 microgram - 375 μg/dosage form, more preferably approximately 0.25 μg - 250 μg/dosage form, more preferably about 2.5 μg - 250 μg/dosage form, more preferably approximately 2.5 ug - 125 μg/dosage form, even more preferably about 2.5 μg - 100 μg/dosage form, most preferably about 2.5 μg - 75 μg/dosage form.

The content of major allergen may be composed of several major allergens depending on the source of all Renov. Usually the number of major allergens corresponds to the range 1-10, for the most part 1-5.

The main allergen can be contained in the extract of the allergen or to be received recombinante. Recombinant major allergens can be used in the same quantities as in extracts of allergens, which contains a major allergen, or in higher doses. Believe that higher doses are more effective, but it is believed that they are associated with the risk of possibly more frequent or more severe side effects.

In the following preferred embodiment of the main allergens include grass allergen group 1, for example, phi p 1, lol p 1, sor h 1, dac g 1, soup d 1, hoi 1 1, pha a 1, the herbal group 2/3 allergen, for example, phi p 2/3, lol p 2/3, grass group 5 allergen, for example, phi p 5, lol p 5, dac g 5, poa p 5, grass allergen group 6, for example, phi p 6, poa p 6 allergen pollen tree group 1, for example, bet v I, AlN g 1, cor a 1, car b 1, tick-borne allergen group 1, for example, der p 1, der f 1, eur m 1, tick-borne allergen group 2, for example, der p 2, der f 2, eur m 2, cat allergen, for example, fel d 1, cedar allergen group 1 and group 2, for example, cry j 1, cry j 2, allergen pollen low and giant ragweed, for example, amb a I, amb a 2, amb a 1, amb t 2.

The effect of the dose-response set, compare with example 6, for solid dosage forms containing allergens that enter through the oral mucosa. When indie is idummy with high sensitivity are a heterogeneous group of subjects, showing different symptoms and different severity of their symptoms when exposed to even the same allergen, the effective dose may vary. Some patients are able to tolerate higher doses without experiencing unacceptable similar effects, whereas others have shown an increased sensitivity. In some cases, you can assign increasing doses to achieve a high dose levels, as commonly believed that higher doses are more effective. Assume that for most of the middle allergic population effective dose of allergen according to this invention preferably will be from 65 BAU/dosage form to 17600 BAU/dosage form, however, the dose to 4 and up to 47,000 BAU can be applied to other patients with allergies. Equally, the dose of allergen extract 0.5 mg 3.75 mg/dosage form, or dose with the contents of the main allergen of 0.05 μg - 375 μg/dosage form may be suitable for medium-allergic individual.

To hypoallergenic variants of the major allergen, i.e. allergens with reduced ability to cause immediate and late phase allergic reactions, dosage form according to the invention preferably contains 10 to 100 times higher primary allergen on the medical form. Such hypoaller the military options may be recombinant or natural origin.

The allergen content of a solid dosage form according to the invention can be determined using normal immune assays such as CIE (cross-immune electrophoresis), RIE (radioimmunoelectrophoresis) and SDS-PAGE (polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulphate) and using immunoassays such as ELISA and specific IgE analysis Magic Lite (LIA)against components of the extract, such as major allergens.

In order to ensure adequate shelf life of the final product, preferred are dosage forms that are not significantly change after fabrication in relation to physical and chemical properties, for example, activity and content of the allergen, the mechanical strength and organoleptic properties.

For purposes of this invention, the stability of the active ingredient, i.e. allergen, judged by the content of the main allergen. In addition, stability is also preferably assessed by definition the activity of the allergen, such as total allergenic activity.

The expression "original antigenic activity" or "original content, at least one of the main allergen" solid dosage forms mean value of allergenic activity or content, at least one of the main allergen in the target Le is arctonoe form after the end of the production process.

The expression "theoretical allergenic activity" or "theoretical content of at least one major allergen" solid dosage forms mean value of allergenic activity or content, at least one of the main allergen" added dose of allergen, for example, in the form of an extract, before be prepared in the form of solid dosage forms.

The loss in the content of the allergen, at least one of the main allergen is preferably less than 50% of the total initial content, more preferably less than 30% of the total initial content, more preferably less than 20% of the total initial content, more preferably less than 15% of the original content, more preferably less than 10% of the initial content, more preferably less than 5% of the original content, even more preferably less than 2% of the original content.

In addition, the loss in total allergenic activity according to the invention described in example 1, and preferably should be less than 50% of the total initial activity, more preferably less than 30% of the total initial activity, more preferably less than 20% of the total initial activity, more preferably less than 15% of the total initial activity.

Usually stability testing performed in accordance with the relevant guidelines and ICH (for example, General course ICH ICQ/Q1AR2 (adapted CPMP, March 2003, issued as CPMP/ICH/2736/99)) and FDA. Conditions of test stability is often referred to as the " terms of zones 1-4. Zone 1 and 2 represents the climatic conditions in the EU, Japan and USA. Usually solid dosage form according to this invention in the final container should preferably be stable at least for 3 months, more preferably at least 6 months, more preferably at least within 12 months, even more preferably, at least within 18 months, most preferably at least for 2 years with long-term conditions 25°C/60 RH, more preferably at intermediate condition 30°C/65 relative humidity, even more preferably with "accelerated conditions of 40°C/75 relative humidity.

To ensure that the solid dosage form will be quite durable during storage and when using the patient, the dosage form should have a certain resistance to the external force, but at the same time solid dosage form must quickly disintegrate in the mouth.

Thus, to confirm the stability of the active ingredient, i.e. a solid dosage form containing the allergen can be OANKOO additional parameters, such as mechanical strength, such as brittleness, tensile strength and maximum load at break. In addition, the stability of solid dosage forms can be evaluated for physical properties, such as time variance and organoleptic properties, such as the appearance of the dosage form.

Named parameters can be estimated, for example, by determining the maximum tensile strength or tensile strength of solid dosage forms of the present invention. From the equation, you can calculate the tensile strength, it is obvious that the obtained value of the tensile strength depends on a number of parameters that are subject to change. For example, the thickness or the diameter of the solid dosage form will help change the value. Therefore, I believe the maximum load at break is even more accurate method to estimate the strength of solid medicinal dosage standard forms of the present invention.

In one embodiment the solid dosage form has a maximum load at break is not less than 0.05 kg and below 0.9 kgf. Preferred are dosage forms that have a maximum load at break, which is 0.05 to 0.9 kgf, more preferably 0,1-0,8 kg, most preferably 0.1 to 0.6 kgf.

In the following embodiment of the present invention t is Erda dosage form has a tensile strength less than 1.0 N/mm 2, more preferably below 0.9 N/mm2.

Preferably bistrotdepierrerue dosage form disintegrates instantly or quickly in the oral cavity upon contact with saliva in order to ensure maximum exposure to the allergen in immunocompetent tissue of the mucous before swallowing. In the preferred embodiment of the solid dosage form disintegrates approximately less than 90 seconds, preferably in less than 60 seconds, preferably in less than 30 seconds, more preferably approximately less than 20, more preferably approximately less than 15 seconds, even more preferably approximately less than 10 seconds in the mouth, even more preferably approximately less than 5 seconds, most preferably about less than 2 seconds in the mouth.

In the preferred embodiment of the invention the compositions of the invention are bistrotdepierrerue solid dosage form comprising a reticulated polymer of allergen and any soluble in water or dispersible in water matrix. The grid is obtained by sublimation of the solvent from the mixture in the solid state, the mixture contains the solution of the allergen and matrix. More preferably the mesh is obtained by freeze-drying.

Pharmaceutically suitable of napolnitel is, forming part of the matrix in bistrotdepierrerue solid dosage form according to the invention, are forming the matrix substances and, in addition, other suitable fillers, such as antacids, thinners, mucoadhesive substances, flavouring agents, taste masking agents, preservatives, antioxidants, surfactants, amplifiers viscosity, dyes, pH modifiers, sweeteners and so on. All of these fillers are selected in accordance with conventional pharmaceutical practice in principle, understandable to experts in the field of preparation of therapeutic agents containing the allergen.

Forming a matrix of matter suitable for use according to this invention include fillers derived from animal or vegetable proteins, such as gelatin/dextrins and soy, proteins of wheat seeds and listblock; resins, such as the Arabian gum, guar, agar, and xanthan gum; polysaccharides; starch and modified starch, alignace; carboxymethylcellulose; karagany; dextrans; pectins; synthetic polymers such as polyvinylpyrrolidone; and polypeptide/protein or polysaccharide complexes such as complexes of gelatin-Arabian gum. Gelatin represent a heterogeneous mixture of water-soluble colloidal macromolecules. Such is heterogene mixture of medium molecular mass distribution can be obtained by hydrolytic action on rich collagen material of animal origin, such as bone, skin, tendons, ligaments, and so forth. Gelatin can be obtained from mammals, such as cattle, pigs, or not mammals, for example, warm-water or cold-water fish. Gelatin can be gidrolizovannykh or non-hydrolyzed, Poperechnaya or Poperechnaya. In addition, they can be thickened or nesihumusho type, gelatin nesihumusho type are usually produced from cold-water fish. In another specific embodiment, the use of starch. Starches are complex mixtures of hydrocarbon polymers.

Other forming a matrix of matter suitable for use according to this invention include sugars such as mannitol, dextrose, lactose, galactose and trehalose;

cyclic sugars such as cyclodextrin; inorganic salts such as sodium phosphate, sodium chloride and aluminum silicate;

and amino acids, containing from 2 to 12 carbon atoms such as glycine, L-alanine, L-aspartic acid, L-glutamic acid, L-hydroxyproline, L-isoleucine, L-leucine and L-phenylalanine.

Solid dosage form preferably contains at least about 50% wt./wt., at least one forming the matrix substance dosed solution. The term "controlled solution"used in this context, means n is a solid amount of drug substances, forming a matrix, allergen and other possible fillers which are at the stage of solidification.

In one embodiment of the invention dosed solution is to form a solid dosage form contains about 5-30% wt./wt., more preferably about 5-20% wt./wt., even more preferably approximately 5 to 12% wt./wt., at least one forming the matrix substance.

The need for the amount of dry matter dosed solution also depends on the size of the tablet. Preferably, the solid dosage form according to this invention have a diameter of from about 3 to about 30 mm, more preferably from about 5 to about 20 mm, Preferably of solid dosage forms according to this invention have a weight from about 1 to about 100 mg, more preferably from about 10 to about 50 mg, most preferably from about 25 to about 35 mg. Preferably solid dosage form according to this invention have a height of from about 0.5 to about 7.5 mm, more preferably from about 1 to about 5 mm.

It is established that bistrotdepierrerue solid dosage form that contains fish gelatin and mannitol as the image of the operating matrix fillers, has the advantage in terms of stability, appearance, low friability, tensile strength, maximum tensile strength and taste in the mouth. In the preferred embodiment bistrotdepierrerue solid dosage forms contain mesh polymer from allergens and substances that form a matrix, such as fish gelatin and mannitol. In order to get the net polymer, it is necessary to adjust the ratio of fish gelatin to mannitol. In the preferred embodiment, the ratio of fish gelatin to mannitol is from about 2:20 to about 20:1, more preferably from about 2:10 to about 10:1, most preferably from about 3:5.5 to about 6.5:3.

In yet another embodiment, the ratio of fish gelatin to mannitol is 4:3.

In another embodiment, the ratio of fish gelatin to mannitol is 6.5:5,5.

In the following embodiment, the ratio of fish gelatin to mannitol is 6.0:5,08.

Solid dosage form according to this invention can be made from the measured amount of the solution, which is first frozen and then dried by freezing. In the preferred embodiment the content of fish gelatin is approximately 2-20% wt./wt. Dosed solution, and the content of mannitol is about 1-20% wt./wt. dosed the second solution. In another preferred embodiment the content of fish gelatin is approximately 2-10% wt./wt. dosed solution, and the content of mannitol is about 1-10% wt./wt. metered solution. In the following preferred embodiment the content of fish gelatin is approximately 3-6,5% wt./wt. dosed solution, and the content of mannitol is about 3-3,5% wt./wt. dosed solution.

In yet another embodiment, the matrix contains about 4% wt./wt. fish gelatin dosed solution and about 3% wt./wt. mannitol dosed solution.

In another embodiment, the matrix contains approximately 6.5% wt./wt. fish gelatin dosed solution and approximately 5.5% wt./wt. mannitol dosed solution.

In the following embodiment, the matrix contains 6,0% wt./wt. fish gelatin dosed solution and 5.08% wt./wt. mannitol dosed solution.

It is established that bistrotdepierrerue solid dosage form containing starch and mannitol as forming a matrix fillers, has a special advantage in terms of stability, appearance, low friability, tensile strength, maximum tensile strength and taste in the mouth. In the preferred embodiment bistrotdepierrerue solid dosage form will win a mesh polymer from allergens and substances, forming a matrix, preferably in the form of pre-gelatinizing starch, such as potato, wheat, maize, corn or rice, and mannitol. To obtain a mesh of polymer, the ratio of starch to mannitol should be adjusted. In the preferred embodiment, the ratio of starch to mannitol is from about 2:20 to about 20:1, more preferably from about 2:10 to about 10:1, most preferably from about 3:5.5 to about 6.5:3.

In yet another embodiment, the ratio of starch to mannitol is 1:1.

Solid dosage form according to this invention is prepared from the measured amount of the solution, which is first frozen and then dried by freezing. In the preferred embodiment the starch content of approximately 2-20% wt./wt. dosed solution, the content of mannitol is about 1-20% wt./wt. metered solution. In another preferred embodiment the starch content of approximately 2-10% wt./wt. dosed solution, and the content of mannitol is about 1-10% wt./wt. metered solution. In yet another embodiment, the starch content of approximately 3-6,5% wt./wt. dosed solution, and the content of mannitol is about 3-5,5% wt./m is S. dosed solution.

In another embodiment, the matrix contains approximately 4.4 percent wt./wt. starch dosed solution and an estimated 4.4% wt./wt. mannitol dosed solution.

Preferably the pH is adjusted prior to the solidification of a solution containing the allergen and the matrix, in order to avoid denaturation of the allergen, precipitation and to provide a stable product. The optimum pH for different allergens in solution covers almost the entire pH scale, which corresponds to their isolationsim points (pi). A mixture of allergens, such as extracts, equally have a pH optimum solubility and stability, certain indicators, such as the concentration of individual allergens in the extract. Therefore, it is possible to consider individual determination of the pH of the preparation according to this invention. The pH optimum for the considered allergen determine when conducting accelerated stability studies of drugs with razlichnimi pH. The scheme of such studies known to specialists in this field.

Preferably the matrix composition containing an extract of the allergen, should lead to pH 3.5-10, more preferably to a pH of 4-9, most preferably to a pH of 6-9.

In addition, this area is well known that the ionic strength may be the measure of the impact on St the mobility dried by freezing solid dosage forms, mainly through its influence on the processes occurring during drying and freezing. It is also known that high ionic strength influences the precipitation. Accordingly, the optimum ionic strength must be installed using procedures well known to specialists in this field. Preferably the ionic strength extract 10 mg/ml is 1-1500 µs/cm (Cm=Siemens), more preferably 300-800 µs/cm, most preferably about 500 µs/cm, for a system containing matrix and the allergen, preferably ionic strength is 1-2000 µs/cm, more preferably about 500-1500 µs/see

Solid dosage forms according to the invention can also contain coloring agents, flavoring agents, pH modifiers or substances that mask the taste. Suitable dyes include red, black and yellow micaceous iron pigment and dye FD & C, such as FD & C blue No. 2 and FD & C red No. 40. Suitable flavorings include extracts of mint, raspberry, licorice, orange, lemon, grapefruit, burnt sugar, vanilla extract, cherries and grapes, and combinations thereof. Suitable pH modifiers include citric acid, tartaric acid, phosphoric acid, hydrochloric acid and maleic acid. Suitable sweeteners include aspartame, ACE is ultam To and traumatic. Suitable substances, taste masking, include sodium bicarbonate, ion exchange resins, compounds with cyclodextrin inclusion, ascorbate or microencapsulated active substances.

Adjuvants usually used to increase the absorption of the allergen, as well as increase the immunostimulatory properties of the allergen.

In another preferred embodiment of the invention bistrotdepierrerue solid dosage form according to the invention does not contain adjuvant.

Also unexpectedly, it was found that there is no need to enter adjuvant in bistrotdepierrerue solid dosage form in order to enhance the immunostimulatory properties of the considered allergen. That is, the solid dosage form considered in the description, can enhance specific immune response, as demonstrated in example 6.

In one embodiment of the invention, at least one adjuvant is administered in a dosage form according to the invention. Examples of suitable adjuvants are aluminum salts, aluminum hydroxide, such as Alhydrogel®, non-toxic fragments of bacteria, cytokines, cholera toxin (and its detoxificaton faction), subunit b of cholera toxin, chitosan, homologous thermolabile fragments of E. coli (and their detoxificaton faction), saponins, bacterial products, t is such as lipopolysaccharide (LPS) and moralily dipeptide (MDP), liposomes (CpG immunostimulatory DNA sequences), homolactic/glycolic ± copolymers in the form of polymer microparticles and so on. The use of adjuvants in pharmaceutical product containing the allergen, for example, vaccines are often explained by the fact that the allergens are not able to penetrareach barrier for the passage. Adjuvants, thus, can serve as amplifiers of suction, or they can act as Immunostimulants. The use of adjuvants, however, may be associated with serious disadvantages, such as not intended stimulation of the different mechanisms of the immune response, systemic lupus erythematosus or impact on the barrier properties of the mucous membranes and, thus, which makes possible the passage of harmful substances. In addition, from a manufacturing point of view, the addition of adjuvant will be another production and other material costs, in addition to the large documentation requirements in respect of registration of the medicinal product.

Non-compacted bistrotdepierrerue solid dosage form can be to some extent mucoadhesives. However, in the preferred embodiment of the invention it may be necessary to add another mucoadhesive fillers to the above-mentioned dosage form, in order to increase the contact time of drug is form from the mucous membrane of the oral cavity. Suitable mucoadhesive fillers are polyacrylic polymers such as carbomer and derivatives carbomer; cellulose derivatives, such as hypromellose, hydroxyethylcellulose, hydroxypropylcellulose, and sodium carboxymethyl cellulose; natural polymers such as gelatin, sodium alginate, pectin and glycerin.

In another embodiment of the invention allergenic dosage form, dissolved in the saliva, it is not necessary to swallow earlier than 3 minutes after the introduction of forms in order to have sufficient contact time, for example, for absorption through the mucous membrane in the oral cavity.

In yet another preferred embodiment of the dosage form, containing the allergen, not diluted in the mouth, for example, when the consumption of liquid, such as water, earlier than 5 minutes.

It is known that the harmful effects or side effects occur in connection with the treatment of allergies. When a specific treatment aimed at changing the current response in sensitized individuals, you may run the risk of induction of side effects in the application of the allergen. Usually the side effects seen with the drug through the mucous membranes of the oral cavity, found in the eyes, nose, mouth, upper and lower respiratory tract and depending on the degree have been fitted the th portability. The most common symptom is itching. Harmful reactions, such as anaphylactic shock, swelling of the upper and lower respiratory tract infections, difficulty breathing, drop in blood pressure, cardiac arrest, should be unacceptable.

Bistrotdepierrerue solid dosage form according to the invention can be produced and packaged in available containers containing many solid dosage forms, i.e. multi-dose containers. Methods and materials are described in U.S. patent No. 5729958 and No. 5343762, are particularly useful. Examples of suitable multi-dose containers are blister packaging entirely of aluminium blister packs of polymers, such as polypropylene, blister packaging, PVC and blister packing formed of sheet PVC/PVdC and hermetically sealed, for example, aluminum, rolled up calandrino Kraft paper, ACLAR® or triplex®.

In one embodiment bistrotdepierrerue dosage form is manufactured and packaged in blister package formed from a sheet of PVC/PVdC and hermetically sealed aluminium, rolled up calandrino Kraft paper. In another embodiment, the blister package is enclosed in an aluminium sachet suitable size, made of aluminum, rolled up calandrino Kraft paper.

Another GP is owenii bistrotdepierrerue dosage form packaged in blister packaging formed by aluminum and hermetically sealed aluminium, rolled up calandrino Kraft paper.

In the following embodiment bistrotdepierrerue dosage form is packaged in a multi-layered blister package made, for example, five sheets of aluminum sheet and hermetically sealed aluminium, rolled up calandrino Kraft paper.

In yet another embodiment bistrotdepierrerue dosage form packaged in blister packing, made of sheet aluminum and hermetically sealed aluminium, rolled up calandrino Kraft paper so that the children were difficult to open blister packaging, such as packaging, too strong for children.

Solid dosage form of this type can typically have a low mechanical strength compared to compressed tablets, due to the private nature of such non-compacted dosage form. This can lead to the release of residual particles containing the allergen, when removed from the blister pocket and during manipulation of patient dosage form. In most situations, it has no value or has a mainly cosmetic. However, it is particularly harmful when the active ingredient is an allergen, so how low the number is as allergen can cause an allergic reaction in prone it the subject or to sensitize previously desencibiliziruuchee of the individual. Typically, the exposure time corresponds to the range of 10 μg/year for allergenic protein, accumulated, for example, from pollen allergen or allergens mites living in dust, which is sufficient to cause sensitization or symptoms.

When the manipulation of solid dosage forms allergens can come in contact with the target organs such as the respiratory tract or the eyes, and cause a response in allergic subjects. One dosage form can contain as many allergen that the subject is exposed in the course of a year or more, depending on the nature of the impact. It is possible to induce ocular symptoms in allergic patients, using the conjunctival allergen provocation. On the basis of studies such stimulation can determine how much of the extract of allergen required to induce conjunctival symptoms. Suppose that the population of patients with severe hay fever, induced by the pollen of grasses, the lowest dose of the extract of grass pollen that causes conjunctival symptoms is 3000 SQ-units/ml × 0.05 ml=150 SQ-units (median value) (S.R.Durham, S.M.Walker, E.M.Varga, M.R.Jacobson, F.O''brien, W.Noble, S.J.Till, Q.A.Hamid and ..Nouri-Aria. Long-term clinical efficacy of grass-pollen immunotherapy. N.Engl. J.Med. 341 (7):468-475, 1999).

To ensure that containing the allergen remains solid dosage form h is released into the environment when opening a multi-dose container, it is important that the fragility of the dosage forms was low as possible without the risk of release of allergen from the dosage form after oral administration.

Thus, in one embodiment approximately less than 500 SQ-units may be released from each solid dosage forms during manipulation, more preferably less than 250 SQ-%, more preferably approximately less than 150 SQ-%, more preferably about 75 SQ-%, more preferably approximately less than 25 SQ-%, most preferably approximately less than 10 SQ-units

In another embodiment, approximately less than 13 BAU can be emitted from each solid dosage forms during manipulation, more preferably approximately less than 7 BAU, most preferably approximately less than 5 BAU, more preferably approximately less 1,95 BAU, more preferably approximately less than 0,65 BAU and most preferably approximately less 0,26 BAU.

In the next incarnation of approximately less than 0.5 micrograms of allergen extract can be extracted from each solid dosage form during the manipulation of her, more preferably approximately less than 0.25 μg of allergen extract, most preferably approximately less than 0.15 μg of allergen extract, more preferably approximately less 0075 micrograms of allergen extract, more preferably approximately less than 0.025 μg of allergen extract, and most preferably approximately less than 0.01 μg of the extract of the allergen.

In yet another embodiment, approximately less than 0.05 µg main allergen may be released from each solid dosage form while touching her, more preferably approximately less than 0.025 μg main allergen, most preferably approximately less of 0.015 µg main allergen, more preferably approximately less 0,0075 µg main allergen, more preferably approximately less than 0.0025 µg main allergen, most preferably approximately less than 0.001 µg main allergen.

In the preferred embodiment of the present invention the residual content of pollen in the multi-dose container after removal of the dosage form does not exceed about 2% of the total content of the allergen, more preferably approximately 0.5% of the total allergen content of a solid dosage form, and more preferably about 0.2% of the total allergen content of a solid dosage form, and most preferably approximately 0.1% of the total allergen content of a solid dosage form, and more preferably about 0.01%, more preferably about 0.005%or more prefer is Ino about 0,003% of the total allergen content of a solid dosage form, most preferably about 0,001% of the total allergen content of a solid dosage form.

Used in the description, the expression "test for fragility" refers to any appropriate test by which to assess the ease with which the solid dosage form crumbles, breaks into pieces, ground to a powder. Suitable test for fragility for use in this invention result below, and it is included in the European Pharmacopoeia, 3rd edition (EP 3-rd ed.), pharmaceutical technical methods 2.9.7. Usually testing the friability of the tablets carried out as described in EP 3-rd ed. 2.9.7. and USP <1216>, and the mass loss rate as an indicator of intact dosage forms. In the test for fragility EP 3-rd ed. 2.9.7. use a drum having a diameter 286 mm, and a depth of about 39 mm Sample of tablets was placed on a sieve No. 100 and any loose residue are removed when you use pressure air or a soft brush. Tablets are weighed and accordingly placed in the drum. Tablets rotate in the drum for 100 periods. Available residues are then removed, as just described, and tablets are weighed again. The result is then expressed as the mass loss and calculated as a percentage of the initial mass. According to USP <1216> you can use a drum with a diameter of between 283 and 291 and a depth between 36 and 40 mm and a rotation of 25± rpm. Accordingly, the integrity of this dosage form can be assessed by visual inspection and measurement of weight of tablets after being exposed this way. Alternatively, due to the low mass of the dosage forms according to this invention, the weighting can be replaced by immunoanalysis specific in relation to the allergen.

It is established that the modified test fragility is a useful tool when assessing what songs are the most stable in terms of density and mechanical strength.

In one embodiment of the fragility of the named solid dosage forms, measured as the number of released allergen, is approximately less than 500 SQ-unit solid dosage form, more preferably approximately less than 250 SQ-unit solid dosage form, more preferably approximately less than 150 SQ-unit solid dosage form, more preferably approximately 75 SQ-unit solid dosage form, more preferably approximately less than 50 SQ-unit solid dosage form, more preferably approximately less than 25 SQ-unit solid dosage form, most preferably approximately less than 10 SQ-unit in solid dosage form in any suitable test is and fragility, where have sufficient external force on the test composition.

In a more preferred embodiment of fragility, measured as the number of released allergen, is approximately less than 500 SQ-unit solid dosage form, more preferably approximately less than 250 SQ-unit solid dosage form, more preferably approximately less than 150 SQ-unit solid dosage form, more preferably approximately 75 SQ-unit solid dosage form, more preferably approximately less than 50 SQ-per solid dosage form, and more preferably approximately less than 25 SQ-unit solid dosage form, most preferably approximately less than 10 SQ-units for solid dosage the form in the test for fragility carried out in accordance with European Pharmacopoeia Pharmacopoeia EP 3-rd.

In an even more preferred embodiment of fragility, measured as the number of released allergen is less than 500 SQ-unit solid dosage form, more preferably less than 250 SQ-unit solid dosage form, more preferably approximately less than 150 SQ-unit solid dosage form, more preferably approximately 75 SQ-unit solid dosage form, more preferably approximately less than 50 SQ-units on the solid the second dosage form, and more preferably approximately less than 25 SQ-unit in solid dosage form, most preferably approximately less than 10 SQ-per solid dosage form, the method comprising the following stages:

a) placing individually sealed blisters, each containing a solid dosage form, in a device for measuring fragility;

b) rotation of the hermetically sealed blister containing solid dosage form, within a reasonable period of time and at a suitable speed;

c) removal of sealed blisters containing solid dosage form;

d) opening the blister and transfer of solid dosage forms and any residue in the container;

e) removal of a solid dosage form from the container, leaving the available balances in the named container;

f) holding the allergen-specific analysis of the mentioned residues with the determination of the content of the allergen in the mentioned residues; and

q) may calculate the percentage content of the allergen in these balances from the General content of the allergen is a solid dosage form.

In another embodiment of the fragility of the named solid dosage form, when measured as the number of released allergen, is approximately less than 0.5 micrograms of allergen extract in solid dosage form in the time which I manipulate it, more preferably approximately less than 0.25 μg of allergen extract in solid dosage form, more preferably approximately less than 0.15 μg of allergen extract in solid dosage form, more preferably approximately less than 0,075 mg of extract of an allergen to a solid dosage form, more preferably approximately less than 0.025 μg of allergen extract in solid dosage form, most preferably approximately less than 0.01 μg of the extract of an allergen to a solid dosage form according to the method comprising the following stages:

a) placing individually sealed blisters, each containing a solid dosage form, in a device for measuring fragility;

b) rotation of the hermetically sealed blister containing solid dosage form, within a reasonable period of time and at a suitable speed;

c) removal of sealed blisters containing solid dosage form;

d) opening the blister and transfer of solid dosage forms and any residue in the container;

e) removal of a solid dosage form from the container, leaving the available balances in the named container;

f) holding the allergen-specific analysis of the mentioned residues with the determination of the content of al is of Elena in the said residues; and

q) may calculate the percentage content of the extract of the allergen in these balances from the General content of the allergen extract a solid dosage form.

In another embodiment of fragility, measured as the number of released allergen, is approximately less than 0.05 μg of the main allergen, more preferably approximately less than 0.025 μg main allergen, more preferably approximately less of 0.015 µg main allergen in solid dosage form, more preferably approximately less 0,0075 µg main allergen in solid dosage form, more preferably approximately less than 0.0025 µg main allergen in solid dosage form, most preferably approximately less than 0.001 µg main allergen in solid dosage form according to the method comprising the following stages:

a) placing individually sealed blisters, each containing a solid dosage form, in a device for measuring fragility;

b) rotation of the hermetically sealed blister containing solid dosage form, within a reasonable period of time and at a suitable speed;

c) removal of sealed blisters containing solid dosage form;

d) scry the Oia blisters and transfer of solid dosage forms and any residue in the container;

e) removal of a solid dosage form from the container, leaving the available balances in the named container;

f) holding the allergen-specific analysis of the mentioned residues defining the content of the main allergen of at least one of the main allergen in these residues; and

q) may calculate the percentage of at least mentioned the main allergen in these balances from the total content of the main allergen is a solid dosage form.

In another preferred embodiment of ways 1 to 100 blisters containing solid dosage form, the apparatus for measuring the sloppiness, as described in the European Pharmacopoeia European Pharmacopoeia V.2.9.7, used in stage a), solid dosage forms rotate within 100 cycles at 25±1 revolutions per minute at the stage b) and the allergen-specific analysis is allergen specific immunochemical analysis in stage f).

In the following preferred embodiment of the method of measuring the fragility of the allergen content was determined by ELISA analysis.

Further, the dosage form must have an attractive appearance. Therefore, as part of quality control bistrotdepierrerue solid dosage form according to the invention is preferably subjected to visual inspection n the example, in respect of color, shape, roughness and defects.

In order to ensure optimal compliance with taking medication, the patient, the dosage form also can be tested for taste in the mouth. For example, do patients dosage form as pleasant when it is placed in the mouth and leave for disintegration.

When allergens have high bioactivity against allergic subjects, i.e. even a small amount can run response, uniformity of content is an important parameter during treatment to ensure, for example, that the sensations experienced by the patient, is played when receiving the same dose. Preferably the variability of allergen forms in multi-dose container corresponds to the limit of ±10%, preferably ±7%, most preferred limit of ±5% compared to the prescribed dose.

Multi-dose container can contain any possible number bistrotdepierrerue solid dosage forms. Preferably, the solid dosage form containing the allergen, packaged and used in the form "groups". Individual solid dosage forms are packaged, spreading in the form of a liquid mixture in individual containers with the subsequent removal of water. Composed blisters can be placed in b is more large plates, and composed of a plate can be packaged and sold together. For example, a container, such as a blister pack, can contain a variety of solid dosage forms, preferably 1-100 solid dosage form, more preferably 1-35 and most preferably 1-10 of solid dosage forms in the blister packaging. In another embodiment stipulate the structure of production, distribution and storage through the use of compiled blister packs, which, for example, can provide 2, 3, 4, 5, 6 or more single prospective courses of treatment. Describe the individual Packed structure is particularly useful for monosovoj therapy and make feasible the treatment regimen described in the description, in which there is no stage of higher doses.

In another embodiment of the present medical service for treatment of allergies or relieve symptoms of allergies. Medication package contains hermetically sealed packaging numerous solid dosage forms, each of which contains an effective amount of allergen. Medication package may contain, for example, at least, 2, 4, 6, 7, 10, 14, 30, 60, 90, 100, 120, 200, 240 or more of solid dosage forms. Medication package can contain a sufficient amount of dosage forms for the full course of treatment or sufficient DL is part of the treatment. Favorably, medication package contains at least the stock one month standard doses.

In another preferred embodiment of the invention all solid dosage forms medication packages contain the same dosage of the allergen, thus eliminating the need for the production, distribution and storage of a wide variety of pharmaceutical dosage forms for the treatment of single Allergy in an individual.

Set containing medication package, in addition, may include instructions relating to the application of solid dosage forms. The instructions may contain a warning statement on the regimen of medicines or other information valuable to the user. The instructions may include, for example, a separate information brochure, article, poster and/or one or more notification printed on the container, such as a box, in which you hold a standard dosage forms. Instructions also can be supplied in the form of a CD-ROM or other read on the computer means, or videotapes.

Preferably, the many solid dosage forms medication package is prepared from a liquid mixture by the method in situ, removing the suspension and/or solvation liquid, which may contain water and/or other institutions the institutions solvents, which quickly dispersed.

In another embodiment of each of the solid dosage forms medication package placed in individual hermetically sealed blisters made in blister pack.

In the next incarnation of solid dosage forms medication package contain gelatin, more preferably fish gelatin.

In yet another embodiment the solid dosage forms medication package contain mannitol.

In another embodiment relating to the medical service, the effective amount of the solid dosage form is approximately 2.5 μg - about 3.75 mg of extract/solid dosage form.

Clinical manifestations and symptoms of allergies are individual and may vary depending on sensitised individuum and allergic. Are common symptoms such as swelling, itching, redness and discharge from the eyes and nose (rhinitis and conjunctivitis), and symptoms associated with upper and lower Airways, such as stercorosus breath, coughing, shortness of breath, skin condition such as eczema, urticaria and itching. Also show other symptoms such as fatigue. Symptomatic treatment is aimed at reducing the severity of symptoms or the impact on the severity of the symptoms or reduce the need for other drugs is the R means, assigned in parallel. Symptomatic medications include antihistamines, such as receptor antagonists H1and H2, intranasal or systemic corticosteroids, non-steroidal anti-inflammatory drugs, nasal decongestants tools, such as agonists of adrenergic receptors. Treatment or attenuation of one or more allergic symptoms or reduce the need for other medication is another objective of the present invention.

Allergy is a common disease of mammals, including humans and animals such as dogs and horses. Thus, another aim of the invention is the provision of a method of Allergy treatment or relief of symptoms of allergies in mammals, including the introduction by the mucosa of the oral cavity an effective amount of allergenic vaccine dosage form comprising (a) matrix and (b)at least one allergen according to any one of the above embodiments.

The treatment, in particular, of seasonal allergies such as hay fever, is usually associated with a particular time of year, when or increased exposure to the specific allergen. Allergenic season varies with the source of the allergen, such as pollen and climatic conditions for the source of al is of Elena in a certain area. Thus, the season for allergen will be different in one part of the world from another part of the world depending on the climate, but usually falls in the same season for the same territory, varying with the actual conditions of the year (see, for example, "Aerobiology and inhalant allergies", Chapter 19, T.A.E.Platts-Mills & W.R.Solomon (Ed. S.Manning) 1993, Mosby-Year Book, St. Louis). Specialists are well aware, when one would normally expect the beginning of the season for a particular allergen in a particular region.

In one embodiment of the invention provide methods of treatment, including pre-season treatment, i.e. the introduction of solid dosage forms according to the invention before allergenic season. In a particularly preferred embodiment of the pre-season period of treatment involves the introduction of solid dosage forms according to the invention for a period of more than 2 weeks prior to Allergy season, more preferably between 4-20 weeks, most preferably between 8-12 weeks.

Another object of the invention is to provide a method for the treatment of allergies or allergic symptoms, which includes the introduction of an effective amount of allergenic vaccine dosage form containing (a) matrix and (b)at least one allergen and, in addition, contains at least one anti-allergic lekarstvennoe means, for example, ant is histamine means, and inhibitors of the synthesis of histamine on any of the above embodiments. Preferably such antiallergic drugs include brompheniramine, cetirizine, Fexofenadine, cyproheptadine at, dexchlorpheniramine, hydroxyzine, ketofen, mequitazine, oxatomide, mizolastine, Bastin, astemizole, carbinoxamine, alimemazine, buclizine, cyclizine, hydrochloric, doxylamine, tritoqualine.

The invention also includes the use of pharmaceutical products containing non-compacted bistrotdepierrerue solid dosage form containing the allergen and at least one forming the matrix substance for the treatment of allergies or relieve symptoms of allergies by introducing through the oral mucosa.

In yet another embodiment of the invention a pharmaceutical product containing a stable bistrotdepierrerue non-compacted allergenic solid dosage form with low brittleness, comprising (a) matrix and (b)at least one allergen and encompasses more antihistaminic agent, used to treat allergies or Allergy symptoms by the introduction of the dosage form through the oral mucosa.

In another embodiment of the present method of Allergy treatment or relief of symptoms of allergies, including (a) medical the service and (b) repeated insertion through the oral mucosa of one or more dosage forms of the drug package until while the symptoms will not get any easier.

In the following embodiment also offer treatment regimen, which is used as a single dose to complete the full treatment sensitization without the use of increasing doses, that is, an increase of various level(s) of the allergen to achieve a certain dose. A specified embodiment is useful because it simplifies and makes more efficient production, distribution and storage of dosage forms, without requiring multiple quantities of doses for the same treatment. In addition, while simplifying treatment improves adherence of patients to treatment regimens that directly leads to greater clinical efficacy.

In another embodiment of the present invention a pharmaceutical product containing oral input solid dosage form comprising a matrix formed of at least one pharmaceutically suitable substance, an effective amount of allergen to desensitization of the person to the allergen, in this dosage form, the content of the allergen is at least approximately 50% of the original content of the allergen after storage for 3 months at 25°C and 60% relative humidity. Preferably named pharmaceutical product is prepared in the form of pellets, tablets, capsules or pills in f is RME capsules.

Bistrotdepierrerue solid dosage form according to the invention can be obtained by sublimation in accordance with the method described in U.S. patent No. 4371516. Accordingly, the solidified solution of the allergen and fillers that make up the matrix, is subjected to sublimation. The sublimation process is preferably carried out by drying the solution with a freezing solution. During the stage of freeze-drying the solution lies in the deepening of the multi-dose container, to obtain a solid form in any desirable form. Multi-dose container can be cooled using liquid nitrogen or solid carbon dioxide. After frozen frozen solution in multi-dose container is subjected to the action of reduced pressure and, if required, controlled application of heat to facilitate sublimation of the solvent.

The invention also includes the use of allergen to produce stable bistrotdepierrerue allergenic non-compacted solid vaccine dosage form with low brittleness, comprising (a) matrix and (b)at least one allergenic form for use in the treatment of allergies or relief of Allergy symptoms.

In another embodiment of the method provide bistrotdepierrerue non-compacted solid and stable drug is authorized forms, suitable for insertion through the oral mucosa, low brittleness, comprising at least one forming the matrix substance and effective dose for desensitization of the individual, at least one allergen, which includes stage

a) preparation of an aqueous solution containing at least one named allergen and at least one substance, which forms the matrix,

b) introducing the solution into one or more recesses in the form

c) freezing and freeze-drying the filled plates using standard conditions of constant temperature and pressure chamber to get called solid dosage form each recess.

In the following embodiments, the method provides receiving bistrotdepierrerue non-compacted solid and stable dosage forms suitable for injection through the mucous membrane of the mouth, having low brittleness, comprising at least one substance, which forms the matrix, and the effective dose for desensitization of the individual, at least one allergen, which includes stage

a) preparation of an aqueous solution containing at least one named allergen and at least one substance, which forms the matrix,

b) introducing the solution into the cavities in the form

c) freeze and the freeze-drying the filled plate, using standard conditions, constant temperature and pressure chamber to get called solid dosage form each recess.

In the preferred embodiment of the method of the forming plate is an aluminum blister plate. In a particularly preferred embodiment of the method of forming the plate is a multilayer, all aluminium blister plate.

In yet another embodiment of the method provides for obtaining pharmaceutical products containing rapidly dispersible non-compacted solid and stable dosage form suitable for administration through the oral mucosa comprising at least one substance, which forms the matrix, and the effective dose for desensitization of the individual, at least one allergen, low fragility, including

1) obtaining a stable bistrotdepierrerue non-compacted solid dosage forms,

2) measure the fragility of the mentioned dosage forms according to the method, which includes stage

a) placing individually sealed blisters, each containing a solid dosage form, apparatus suitable for measurement of fragility;

b) rotation of the hermetically sealed blister containing solid dosage form, for compliance is adequate period of time and at a suitable speed;

c) removal of sealed blisters containing solid dosage form;

d) opening the blister and transfer of solid dosage forms and any residue in the container;

e) removal of a solid dosage form from the container, leaving the available balances in the named container;

f) holding the allergen-specific analysis of the mentioned residues defining the content of the main allergen of at least one of the main allergen in these residues; and

q) calculating the percentage, at least, mentioned the main allergen in these balances from the total content of the main allergen of the whole solid dosage forms,

establishing whether dosage form requirements low fragility, and

3) repeat 1) and 2) until such time as the requirements of the dosage form will not be executed.

Immunotherapy with the introduction through the oral mucosa can be considered as a means of induction of tolerance and induction of vaccination through the mucous. The mucous membrane of the mouth is rich in dendritic cells with strong potential for the presentation of antigen. I believe that dendritic cells ProcessInput allergens, and then migrate to the local lymph nodes, where they present peptides derived from an allergen, the allergen-specific T-latcham. I believe that during sublingual immunotherapy describes the interaction of dendritic cell-T-cell stimulating T cells with regulatory capacity or increases the ratio of allergen specific Th1 cells to the allergen-specific Th2 cells. A number of immune parameters recorded at the time of vaccination against Allergy, can be suitable markers of exposure and the effectiveness of treatment, separately or in combination, respectively. Mentioned markers include a system antitelomerase and antitelomerase in the mucous membrane, for example, specific antibodies IgA, IgG and IgE; levels of cytokines, such as gamma-INF, IL-2, IL-4, IL-5, IL-10, IL-12 and TNF-alpha in blood or mucous secrets; activation, chemotaxis, proliferation, signal transmission, the formation of cytokines and other regulatory T cells, Th1 cells, Th2 cells, CDS cells, other subpopulations of T-cells or b-cells, or NK-cells, and the expression of cell surface markers, such as CD markers (clusters of differentiation), for example, CD4, CDS, CD23, CD25, CD62L, CLA, beta, CCR9, CD69, CD45RO, CCR3, CXCR5, the function of effector cells, such as the total content of histamine in basophils) basophils; the number of eosinophils, basophils, lymphocytes, monocytes in the blood, tissue and secrets; the release of mediators of eosinophils, basophils, lymphocytes, monocytes, cytokine production, activation, chemotaxis is, proliferation, signaling, and other responses.

In the preferred embodiment of the vaccine according to this invention is characterized by a profile, which you can install one or more of the following immune changes; increased response allergen specific IgG, increased response allergen specific IgA, reduced the allergen-specific IgE response, a small number of local side effects; reduced the allergen-specific effector responses of eosinophils, basophils, lymphocytes and/or monocytes; the induction of regulatory T-cells, increased the ratio of allergen specific Th1 cells to the allergen-specific Th2 cells, induction of other cells with regulatory potential, reduced response of allergen specific Th2 cells.

Allergy is also known as a disease of animals, especially domestic animals and ship animal companions. In this area it is known that they are developing allergies to the many sources of allergens, including grass, house dust mites and parasites. The blood parasites, that is, invasion of blood-sucking insects known to cause allergic reactions, called flea allergic dermatitis (FAD). In the preferred embodiment of allergens for animal vaccines include allergens, taking place or carried by parasites, such as E. theparasite (for example, fleas, ticks, mosquitoes, flies), poison parasitic worms (such as helminth parasites in heart, for example, Dirofilaria, or onchocerciasis, for example, Onchocerca], and mites that live in household dust. More preferred are allergens saliva of fleas, such as Ctenocephalldes, for example, .canis and .fells, hard ticks such as Ixodes, Arnblyomma, soft ticks, such as Ornithodoros, and small two-winged insects such as Culicoldes.

EXAMPLES

Abbreviations:

API: active protein ingredient

ELISA: enzyme-linked immunosorbent assay

DDT: dithiothreitol

HRP: horseradish peroxidase

LIA: analysis of specific IgE Magic Lite

LITE-agent: Fluorescent labeled anti-IgE

PMP: paramagnetic particles

SDS-PAGE: polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate

TMB: tetramethylbenzidine

Example 1. Allergenic vaccine containing the extract of pollen of grass Phleum prafcense and fish gelatin Composition

Table 1
IngredientsUnitsDosage form 1Dosage form 2Dosage form 3Function
The medicament is i.i.d. substance: API
Phleum pratenseSQ-units250025000the 125,000
mg extract0,00470,0470,235
Other ingredients:
Purified watermga sufficient amount of to 250 mgenough
250 mg
a sufficient amount of to 250 mgsolvent
Gelatin (fish gelatin with standard molecular weight, Croda UK)mg101010matrix
Mannitol mg7,57,57,5matrix
Sodium hydroxidemgenoughenoughenoughbringing the pH to 7.5

An extract of the herb

Extract of grass pollen were prepared in accordance with the method described Ipsen and Lowensten (1983) Jour. Allergy. Clin. Immunol. 72:2, str-159. The undersized grass pollen were extracted in ammonium bicarbonate for 20 hours at 5°C. the Substance is in the form of particulates were removed by centrifugation and the supernatant were dialyzed against water (3 times), liofilizirovanny and kept in the cold before the reconstruction.

Solid dosage form

Manufacturing process

1. Mannitol was added to the aliquot of purified water (not less than 50% of the total boot needs) and left to dissolve.

2. Gelatin was added to a solution of mannitol and the solution was stirred on a magnetic stirrer until then, until the gelatin has dissolved completely.

3. A second aliquot of purified water (not more than 35% of the total) used for the reconstruction of allergen extract in capsules. The reconstructed allergen extract was added to a solution of m is nite-gelatin.

4. the pH of the composition of the main mass was brought to pH 7.5 using a freshly prepared sodium hydroxide solution (3% wt./wt.).

5. An additional amount of purified water that is required to complete the preparation of forms, counted and added into the main mixture.

6. The solution was made certain doses in pre-cooked blister packaging. The solutions were dosed out at a temperature environments.

7. After dosing filled blister packaging was passed through a cooled with liquid nitrogen tube. All frozen products are immediately placed for safekeeping in the cold to freeze-drying. The blocks were dried by freezing, using standard conditions - constant temperature and pressure chamber.

8. Dried by freezing the blocks hermetically closed by a closing of a thin foil, and finally Packed in a sachet.

Solid dosage form had an average weight of 18 mg and the average diameter of 11 mm

A brief description of the analytical methods

Identity (ID), protein profile. Protein profile was determined using SDS-PAGE on a system Novex Mini-Cell Xcell II (Invitrogen) according to manufacturer's instructions. Briefly, samples were diluted with buffer to the sample with added regenerating agent (0.5 M DDT) and kept at 70°C for 10 minutes and cooled for 5 minutes. Sample NR the internal control and standard molecular marker (10 RAD) per well was applied onto 4-12% bis-triradiate NuPAGE gel. Electrophoresis was carried out at 200 V for approximately 35 minutes. Subsequently, the gel was stained with silver. Protein pattern should be similar to the picture of internal control.

Visual inspection

All blocks were subjected to visual inspection, for example, with respect to color, shape, roughness and defects to ensure the appropriate type.

The disintegration. The test was performed as described in the European Pharmacopoeia (3rd edition) or USP (U.S. Pharmacopoeia).

The water content. Residual water was determined using a titration Karl Fischer. The method provides a quantitative assessment of water content in the sample based on the principle that a certain number of I2leads to the transformation of an equivalent amount of N2O.

Briefly, 1-3 solid dosage form in ampoules tested in three repetitions in the Karl Fischer titrator according to the manufacturer's instructions along with the unknown samples (4 on experience), a KF standard samples, see example 10.

The total allergenic activity. The test was performed using LIA (described Eiken et al., Allergy 1992, 47:495-497), which is a competitive immunoassay. 100 μl of monoclonal anti-IqE-human antibodies associated with paramagnetic particles (PMP) (ADVIA Centaur PMP, ALK-Abello A/S, Denmark), washed × 3 and added 100 mkula serum of a patient with IgE-antibodies, specific to Phleum pratense, and incubated on the vibrator for 2 hours at 2-8°C, while specific IgE bound PMP. PMPs were washed 3 times with buffer containing gelatin, to remove IgG antibodies. Ten solid dosage forms was dissolved in gelatin buffer was prepared by dilution with 625 SQ-units or 1250 SQ-units for the tablet. Samples or controls with known content biotinylated API Phleum pratense was applied and incubated overnight with shaking at 2-8°C. Samples and biotinylated API competed for IgE-binding sites, when the concentration of allergen in the sample increased, the amount of bound biotinylated API fell. After incubation, the samples were washed × 3 in buffer containing gelatin, and used the LITE reagent, for example, chemiluminescent compound of ester acridine associated with streptavidin (ADVIA Centaur Lite Reagents, ALK-Abello A/S). Samples were incubated for 2 hours on the vibrator at 2-8°C, washed in gelatin buffer × 3 and read in a luminometer. The response is inversely proportional to the concentration of allergen in the sample.

The content of the main allergen. Testing was performed using the ELISA according Obispo et al., Allergy, 1997, 52, pp.806-813. Using ELISA analysis was determined by the concentration of the main allergen 5 Phleum pratense (Phi p 5). Two monoclonal antibodies (ALK-Abello A/S, DK), interacting with various the and epitopes on the molecule Phi p 5, was layered in microtiter tablet overnight at 4°C. After washing (4 times with the washing buffer, 0.1 M PBS, 0.05% tween-20) and blocking tablet blocking buffer (2% casein buffer) was applied to the samples/controls, which are then contacted with the antibodies. After washing again (4 times with the washing buffer into the wells inflicted biotinylated rabbit polyclonal antibodies (ALK-Abello A/S, DK) against antigens Phleum pratense and left to interact.

After 4 times washing, the washing buffer in the wells was made streptavidin associated with HRP (horseradish peroxidase (DAKO, Denmark), and left to interact for 1 hour at room temperature (shake). After washing 4 times with the washing buffer was made substrate (TMB, WHO EN TES) enzyme HRP and left to interact for 20 minutes, then the reaction was stopped with 0.5 N. sulfuric acid. The resulting staining was measured at 450 nm in a spectrophotometer, for example, the counter Multi-label counter Victor 2.

The fragility

The fragility bistrotdepierrerue dosage forms were evaluated using the following method.

Hermetically sealed blister plate containing 10 blisters, each blister contains solid dosage form, cut separately on 10 individual blisters and each strip was placed in the apparatus for measuring fragility,as described in EP 3-rd ed. V.2.9.7 and blisters were rotated 100 cycles at 25±1 rpm. Individual blisters were removed, opened and the solid dosage form was transferred into a suitable container. Then the solid dosage form is removed from a container, leaving the available balances in the named container. Immunochemical allergen specific assay (ELISA) was performed to determine the amount of allergen in the residuals (see above).

The results of stability studies

Example 2. Allergenic vaccine containing the extract of pollen of grass Phleum pra tense and starch

The composition of

Method of cooking

Carried out as in example 1, except that the pre-gelatinizing starch was added instead of gelatin (source - fish). Solid dosage form had an average weight of 19 mg and the average diameter of 11 mm

A brief description of the analytical methods

The same as in example 1.

The results of stability studies

Example 3. Allergenic vaccine containing the herbal extract and fish gelatin

Method of cooking

The same as in the example is 1.

Solid dosage form had an average weight of 30 mg and the average diameter of 12 mm

A brief description of the analytical methods

The same as in example 1, except that the fragility and stability was not determined.

Results studies

The results give an idea of the embodiment of the solid dosage form containing the allergen in three different doses of the herbal extract of the allergen in the material forming the matrix, consisting of a 6.5% fish gelatin and 5.5% mannitol. After production the content of the allergen and the activity of the allergen in dosage forms were within acceptable limits (see below). In addition, the results show that all dosage forms have a water content within the preferred range of 4-7%.

Results

As can be seen from examples 1, 2 and 3, it is possible to produce bistrotdepierrerue solid vaccine dosage form containing the allergen, which disintegrate instantly. Found that the loss of the total content of the extract is valid even visual inspection has revealed the remains of some of the blister packs (mainly more for the matrices containing starch), the amount of residue, i.e. the loss of the allergen content was within acceptable limits, i.e. less than 0.5 µg extrac the and. Thus, it is possible to produce non-compacted bistrotdepierrerue solid dosage forms with low fragility containing allergens.

The results of the stability studies showed that the composition is stable at room temperature and at elevated temperature and humidity within nine months. The content of the allergen and the total allergenic activity remained unchanged (within fluctuations of research and in accordance with EP (3rd edition) by allergenic foods; total allergenic activity was 50-200% of theoretical value, the content of the main allergen was 65-135% of theoretical value).

All the batches produced were subjected to visual inspection and how it was discovered, conforms to the valid range.

Example 4. Vaccine compositions containing the allergen

Received solid vaccine dosage form containing the allergen, with various proportions of the substances forming the matrix.

All dosage forms having a uniform diameter of 12 mm, was obtained in the blister package, as described earlier. All dosage forms quickly disintegratable and were robust when evaluated on appearance, tensile strength and maximum load on the gap.

All dosage fo what we having a uniform diameter of 12 mm, was obtained in the blister package, as described earlier.

All dosage forms quickly disintegratable and were robust when evaluated on appearance and maximum load on the gap.

Example 5. Uniformity

Dosage forms in accordance with the composition and production that described in example 1, were tested regarding the content uniformity of the allergen. The content of the allergen was identified as the homogeneity of the activity of pollen grass Phleum p 5 using ELISA as described in example 1 for dosage forms containing 25000 and the 125,000 SQ-units respectively. Compared the 10 individual items from the blister package, the results are presented in table 13 and 14.

All the variations were within the acceptable range, and a good uniformity of content of the allergen.

Example 6. The introduction of the vaccine pollen grass Phleum pratense dogs

Dogs were equally distributed in terms of gender in each studied group and give them a certain dose in accordance with table 15.

Dogs sublingual injected dose listed in table 15. Dosage form was placed under the tongue and mouth dog kept closed, to cause a dissolution of the dosage form. LM is now received the drug once a day for a period of 4 consecutive weeks. Blood samples were taken from all dogs in each group after the treatment period. 4 dogs in the placebo group who received high-dose, respectively, was recovered during a period of 4 weeks, after which they took another blood sample.

Way

Determined IgG specific to Phleum pratense (Phi (p), or in serum or plasma as follows: ELISA-plates (Costar) were coated 10 μg/ml of extract Phi p over night at 4°C. the Tablets were washed 4 times with 1 minute absorption between them and blocked against non-specific binding of 2% casein buffer for one hour at room temperature. Individual samples of serum or plasma was diluted in polypropylene tablets, endured in tablets for ELISA and incubated for two hours at room temperature. After washing the HRP-labeled anti-dog IgG (ICN) was added to the ELISA-plates and incubated for one hour at room temperature. After another washing TMB was added to the ELISA-tablets covered and incubated for 20 minutes at room temperature. The reaction was stopped with 0.5 M sulfuric acid. The optical density (OD) was measured in a spectrophotometer at 450 nm.

The OD values at a dilution of 1:200 was compared for dogs three groups: placebo, 25000 SQ/dose and 500000 SQ/dose. The statistical difference between the three groups was calculated according to the iteria ranked number Mann-Whitney, which is a nonparametric test that compares two unpaired groups. Dogs treated with 500000 SQ-units had a higher average value than dogs treated as 25000 and placebo, indicating specific antibody responses.

Results

By P-values on the criterion of Mann-Whitney presented in table 16.

Table 16
GroupA value of P
Placebo vs 25000SQ-units/dose0,059
Placebo against 500000SQ-units/dose0,004

P - level ≤0.05 is the significance with 95% confidence.

There are clearly significant differences between the groups receiving placebo and 500000 SQ-units/dose, indicating that sublingual treatment with 500000 SQ-units/dose for 4 weeks gives a higher humoral level of specific IgG. There is a borderline significant difference between the groups receiving placebo and 25000 SQ-units/dose, also indicating that such treatment with 25000 SQ-units/dose gives humoral level of specific IgG, although weaker than treatment 500000 SQ-units/dose.

Example 7. The introduction of the vaccine pollen Tr is you Phleum pratense subjects with allergic

Patients with allergies, both women and men aged 18-65 years, diagnosed with Allergy to grass pollen, introduced sublingual dose in the form of one, two or three single doses and/or multiple doses in solid dosage form containing an extract of grass pollen, in accordance with example 1, in a randomized double-blind placebo-controlled of the study.

Safety/tolerance was evaluated with increasing single doses. Single doses of placebo 2500, 25000, 75000, 125,000 and 375000 SQ-units were introduced step on the way to "increase the dose", using a combination of placebo and active tablets (12 mm in diameter and approximately 18 mg dry weight)to obtain the desired dose. Treated forty-seven patients with Allergy to grass pollen. Dosage forms were placed under the tongue and held for 1 minute before swallowing. Eating and drinking was banned within 5 minutes after application of solid dosage forms. Patients were followed for 2 hours in relation to the onset of symptoms. All side effects were recorded and after each dose in patients was determined tolerance on a scale of "visual similarity". Found that dosage form containing doses were well tolerated up to and including the 125,000 SQ-units, because the side effects were mostly weak the severity and limited symptom of itching in the mouth and throat. Side effects were also noted in the placebo group. "Itching in the mouth" was often noted at the higher dose, for example, the progression of side effects correlated with the increase of the doses.

In addition, safety/tolerance to repeated doses tested against three selected doses of 2500, 25000, and 75 000 SQ-u and placebo. Forty-seven patients with Allergy to grass pollen, distributed in four groups of comparable size, gave daily sublingual dosage form within 8 weeks. The combination of three tablets containing placebo, 2500 and/or 25000 SQ-units (12 mm in diameter and approximately 18 mg dry weight), was used to obtain the required dose. Recorded side effects, and symptoms were recorded in the diaries of patients. It is established that the dose contained in the dosage form, was well tolerated in all three active treatment groups. Side effects and symptoms were more frequently observed at the high dose.

Thus, testing of solid dosage forms suitable for clinical use in therapy with increasing dose and therapy with pay repeatedly injected dose.

Example 8. Allergenic vaccine containing the extract of pollen of grass Phleum pratense and fish gelatin

Solid dosage forms, which are described in table 1 of example 1 and was obtained according to example 1, hranilis for 12 months at 25°C./60% relative humidity and were evaluated in the study the appearance, disintegration, water content, uniformity of mass, identity (protein profile), the content of the main allergen and the total allergenic activity. All analyses were performed as described in example 1. Presents the average values of the definitions made in two copies on the pool of 10 tablets, if not specified.

Visual inspection

Any changes in the appearance of the tablets were not observed during the study.

The disintegration

No noticeable changes over time that decomposition was not observed during the study. All the analyzed samples getintegervalue immediately.

Uniformity of mass

No significant changes in the homogeneity of the mass is not observed during the study (evaluation of 20 tablets).

Water content

No significant change in water content is not observed during the study.

Identity in SDS-PAGE

No dramatic changes in the protein profile were not observed during the study; the samples were similar to the control in all the studied periods of time.

The total allergenic activity

No significant loss of total allergenic activity was not determined for tablets (changed on 105-119% theoretical content for various activities for 12 months, size, catariacoltsfoot limit deviations research).

The content of the main allergen

No significant loss of content of the allergen, which was determined by the content of the main allergen, did not for tablets (changed on 99-104% theoretical content for various activities during the 12 months of storage, the values that are within the deviation research).

Example 9. Allergenic vaccine containing the extract of pollen of grass Phleum pratense and fish gelatin

The composition is the same as the composition described in example 1, table 1.

Solid dosage form obtained according to example 1 was stored for 18 months at 25°C./60% relative humidity and were evaluated for appearance, dosage forms, i.e. tablets, and in the study of time disintegration, water content, uniformity of mass, identity (protein profile), the content of the main allergen and the total allergenic activity. All analyses were performed as described in example 1. Presents the average values of the definitions made in two copies on the pool of 10 tablets, if not specified.

For solid dosage forms containing 25000 SQ-units/solid dosage form, and I were the only study ID (identity). The same character set ID after storage for 18 months is compared with 0 months (data not shown).

Found that the solid dosage form is stable, i.e. the content of the allergen and the total allergenic activity remain unchanged (within the scatter analysis and according to the EP, 3rd edition, monograph. Food allergens; common allergenic activity is 50-200% of theoretical volume, the content of the main allergen - 65-135% of theoretical value) after storage for 18 months at 25°C./60% relative humidity. In addition, the study did not observe any changes in the appearance of solid dosage forms for all the studied doses of allergen. In addition, the study did not observe any changes in the homogeneity of masses tested dosage forms. As for the water content did not observe any noteworthy changes, and the water content corresponded to the preferred range of 4-7%.

Example 10. Allergenic vaccine containing extract of grass pollen Phlevm pratense and fish gelatin

The composition of the solid dosage forms are presented in table 9 of example 1.

Solid dosage forms was obtained according to example 1, and the stability studies submitted.

All tests were performed according to example 1.

The results of stability studies

Table is CA 19
Product2500 SQ-units/lekarstvennie form
Storage conditions:25°C/60% RH
Tests:Visual inspectionThe disintegrationThe total allergenic activity (LIA)The content of the main allergen (ELISA)Water content (%)
Sampling (month)
01 second129%82%5,0%
11 second87%98%5,3%
31 second130%116%61 second97%100%5,2%

Storage condition:40°C/75% relative humidity
11 second97%90%5,2%
31 second124%114%5,5%
61 second101%93%5,9%

Table 20
Product25000 SQ-units/dosage form
Storage conditions:25°C/60% relative humidity and
TestsVisual inspectionIdentity (SDS-PAGE)The disintegrationThe total allergenic activity (LIA)The content of the main allergen (ELISA)Water content (%)
Sampling (month)
0such control1 second101%93%4,7%
1I have not measuredsuch controlI have not measuredI have not measuredI have not measuredI have not measured
3I have not measuredsuch controlI have not measuredI have not measuredno metering is Lee I have not measured
6I have not measuredsuch controlI have not measuredI have not measuredI have not measuredI have not measured

The quality drug, forms to be judged by the results of visual inspection dosage forms (i.e. tablets), determine the time of disintegration, water content, uniformity of mass, identity (protein profile), the content of the main allergen and the total allergenic activity (not all data shown).

It is established that solid dosage form for all doses are stable, that is, the content of the allergen and the total allergenic activity remained unchanged (within the fluctuation (variation) research and according to the EMEA, 3rd edition, monograph. Food allergens: total allergenic activity - 50-200% of theoretical value, the content of the main allergen - 65-135% of theoretical value) after storage for 6 months at 25°C./60% relative humidity and 40°C/75% relative humidity. In addition, during the study did not observe any changes in the appearance of solid dosage forms for all tested doses of allergen. Further, during the study did not observe any changes in the uniformity of mass for all tested formulations. With regard to water content, the study did not reveal any noteworthy changes. Watched a small tendency to increase the water content during storage at 40°C./75%relative humidity for all doses, although the water content in all tested samples was within the preferred range of 4-7%.

Example 11. Determination of water content and water activity in allergenic formulations containing the extract of pollen of grass Phleum prateense and fish gelatin

The composition of

Storage conditions40°C/75% relative humidity
1such controlI have not measuredI have not measuredI have not measuredI have not measured
3such controlI have not measuredI have not measuredI have not measuredI have not measured
6such controlI have not measuredI have not measuredI have not measuredI have not measured
Table 22
Name of ingredientThe composition of R (5,5% fish gelatin)Composition F (4% fish gelatin)Function
Purified waterenough to 250,000 mgenough to 250,000 mgsolvent
Phleum pratense2500, 25000 or 75000 SQ-units2500, 25000 or 125000 SQ-unitsthe active ingredient
0,0047 mg 0,047 mg, 0,141 mg0,0047 mg 0,047 mg, 0,235 mg
Gelatin (source of fish)16 mg10 mgmatrix
Mannitol 14 mg7.5 mgmatrix
Sodium hydroxideenough to rn,5a sufficient amount of to pH 7.5the pH modifier

Solid dosage forms was obtained in accordance with example 1.

Water activity of various solid dosage forms was measured on gyroscope Rotronic Hygroskop BT-RS1 (Rotronic ag, Switzerland). 10 tablets were used for each measurement. Stable readout of the signal meant that reached equilibrium, and the relative humidity is subsequently converted to water activity using the following dependency:

where

awmeans water activity of the sample,

Pwmeans the partial pressure of water vapor above the sample,

Pw* is the water vapor pressure above pure water and

RHequ(ERH tea: equilibrium relative humidity) mean relative humidity of the sample.

Used comonomer 756 Karl Fischer thermostat Oven Sample Processor 774 (Metrohm, Herisau, Switzerland) to determine the water content in the tablets. 1-3 tablets were placed in glass vials and tightly closed lids, covered with PTFE (Metrohm, Herisau, Switzerland). Experienced and the pools were then placed in a thermostat Oven Sample Processor 774 (Metrohm, Herisau, Switzerland) and any moisture present in the samples evaporated at a temperature of 130°C. the Evaporated moisture is carried into the reaction cuvette containing the reagent Hydranal®-Coulomat Oven (Riedel-de-Haen), in nitrogen atmosphere and subsequent quantification of the number of released water was carried out by the method of Karl Fischer titration in accordance with the manufacturer's instructions. The results are presented in table 24.

0,45
Table 23
Water activity and water content of different allergenic dosage forms containing the extract of pollen of grass Phleum pratense and fish gelatin
SampleWater activityWater content (%)
NAverageSDNAverageSD
Placebo30,460,02235,59to 0.060
Composition R 2500 SQ-units20,0043is 4.930,071
Composition R 25000 SQ-units20,410,00134,670,021
Composition R 75000 SQ-units20,410/0053of 4.660,053
Composition F 2500 SQ-units10,44-35, 450,070
Composition F 25000 SQ-units10,46-35,190,055
Composition F 125000 SQ-units10,44-34,800,056
3D the mill is artee deviation

All solid dosage forms have an average water activity between 0,41-0,46, although the water content of some forms were more than 5%.

Example 12. Allergenic vaccine containing the extract of pollen from Phleum pratense

The composition of

Table 24
IngredientsComposition % wt./wt.Dosage form 1, placeboDosage form 2,
25000
Dosage form 3, 75000
Fish gelatin (North, Canada)6,014 mg14 mg14 mg
Mannitol5,0812,7 mg12,7 mg12,7 mg
API (extract of grass pollen)025000 SQ-units75000 SQ-units
NaOHa sufficient amount of to pH 7.5a sufficient amount of to pH 7.5sufficient the number to a pH of 7.5 a sufficient amount of to pH 7.5
Purified watera sufficient amount of to 250 mga sufficient amount of to 250 mga sufficient amount of to 250 mga sufficient amount of to 250 mg
Total %/full wet weight100250 mg250 mg250 mg
Dry weight27.7 mg27.7 mg27.7 mg

The composition was obtained as described in example 1, except that used fish gelatin from the Northern area of Canada. Solid dosage form had an average diameter of 13 mm

Table 25
The dosage formsFriability (% loss of the total content of the extract (API))
25000 SQ-units0,000*
75000 SQ-units0,000*

The results give an idea about abuses the embodiment containing the allergen solid dosage form, embodying two different doses of the herbal extract of the allergen in the material forming the matrix, and forming a matrix substance, consisting of 6,0% fish gelatin and 5.08% mannitol. Dosage forms tested on the fragility of the methods described in example 1. The results showed that the compositions are stable against fragility, defined as the release of the allergen.

1. Pharmaceutical product, suitable for the introduction of the allergen, including:
bistrotdepierrerue solid dosage form suitable for administration through the mucosa of the oral cavity, comprising:
(a) matrix, obtained by freeze-drying from a solution containing 3-6,5% wt./wt. pre gelatinizing starch and 3-5,5% wt./wt. mannitol or from a solution containing 2-10% wt./wt. fish gelatin and 1-10% wt./wt. mannitol and
(b) an effective dose of the allergen to hyposensitization of the individual to the allergen,
where this solid dosage form contains an extract of the allergen in the amount of from about 0.5 μg to 5 mg of extract per solid dosage form, or where the specified solid dosage form contains an extract of the main allergen in the amount of from about 0.05 mg to 500 mg of extract per solid dosage form.

2. Pharmaceutical product according to claim 1, which is the form of non-compacted solid dosage forms.

3. Pharmaceutical product according to claim 1, where
(c) loss of the content of the allergen in the said dosage form is less than 50% of the original content of the allergen after storage for 3 months at 25°C and 60% relative humidity, and
(d) loss of allergen content of these dosage forms is approximately less than 0.25 μg of allergen extract in the study with a test for fragility.

4. Pharmaceutical product according to claim 1, where
(c) loss of the content of the allergen in the said dosage form is less than 50% of the original content of the allergen after storage for 3 months at 25°C and 60% relative humidity, and
(d) loss of allergen content of these dosage forms is approximately less than 0.025 μg main allergen in the study with a test for fragility.

5. Pharmaceutical product according to any one of p or 4, the fragility of which was measured using the test for brittleness, comprising the following stages
(a) an individual sealed blisters, each containing a solid dosage form, apparatus suitable for measurement of fragility;
(b) rotation of the hermetically sealed blister containing solid dosage form, within a reasonable period of time and at a suitable speed;
(c) removal hermetically C is covered blister, containing solid dosage form;
(d) opening the blister and transfer of solid dosage forms and any residue in the container;
(e) removing the solid dosage form from the container, leaving any loose debris in the named container;
(f) the implementation of the allergen-specific analysis in these residues, determining the content of the allergen in the mentioned residues; and may calculate the percentage content of the allergen in these balances from the General content of the allergen is a solid dosage form.

6. Pharmaceutical product according to claim 5, in which
(a) use from 1 to 100 blisters containing solid dosage form,
(b) use the apparatus for measuring fragility, which is described in the European Pharmacopoeia 2.9.7,
(c) solid dosage forms rotate within 100 cycles at 25±1 revolutions per minute, and
(d) allergen analysis is allergen specific immunochemical analysis.

7. Pharmaceutical product according to claim 6, and allergen analysis is a solid phase enzyme-linked immunosorbent assay.

8. Pharmaceutical product according to claim 1, which contains from about 2.5 μg to about a 3.75 micrograms of allergen extract.

9. The pharmaceutical product of claim 8, which contains from about 2.5 μg to about 2.5 mg extras is as allergen.

10. Pharmaceutical product according to claim 9, which contains from about 25 μg to about 2.5 mg of the extract of the allergen.

11. The pharmaceutical product of claim 10 which contains from about 25 mg to about 1.25 mg of the extract of the allergen.

12. Pharmaceutical product according to claim 11 which contains from about 25 μg to about 1 mg of the extract of the allergen.

13. Pharmaceutical product according to item 12, which contains from about 25 μg to about 750 μg of allergen extract.

14. Pharmaceutical product according to claim 1, which contains from about 0.25 microgram to about 0.25 mg of the main allergen.

15. Pharmaceutical product 14, which contains from about 2.5 mg to about 0.25 mg of the main allergen.

16. Pharmaceutical product according to clause 15, which contains from about 2.5 μg to about 0.125 mg the primary allergen.

17. Pharmaceutical product according to clause 16, which contains from about 2.5 μg to about 0.1 mg of the main allergen.

18. Pharmaceutical product 17, which contains from about 2.5 μg to about 75 μg of the main allergen.

19. Pharmaceutical product according to claim 1, which contains a dose of from about 65 to about 15000 BAU.

20. Pharmaceutical product according to claim 19, which contains a dose of CA is approximately 650 to approximately 15000 BAU.

21. Pharmaceutical product according to claim 20, which contains a dose of from about 650 to about 6000 BAU.

22. Pharmaceutical product indicated in paragraph 15 contains the main allergen is grass pollen selected from the group consisting of allergen grass group 1 allergen grass groups 2/3, allergen grass group 5 and grass allergen group 6.

23. Pharmaceutical product according to item 15, containing the main tick-borne allergen selected from the group consisting of mite group 1 allergen and mite group 2 allergen.

24. Pharmaceutical product according to item 21, which contains a dose of from about 650 to about 4700 BAU.

25. Pharmaceutical product according to paragraph 24, which contains a dose of from about 650 to about 3500 BAU.

26. Pharmaceutical product according to claim 19, in which the allergen is an allergen is grass pollen.

27. Pharmaceutical product according to claim 1, in which the loss of the content of the allergen is approximately less than 30% of the initial content after storage for 3 months at 25°C and 60% relative humidity.

28. Pharmaceutical product according to item 27, in which the loss of the content of the allergen is approximately less than 20% of the initial content after storage for 3 months at 25°C and 60% relative humidity.

29. Pharmaceutical product p in which the loss of the content of the allergen is p is blithedale less than 15% of the initial content after storage for 3 months at 25°C and 60% relative humidity.

30. Pharmaceutical product according to clause 29, in which the loss of the content of the allergen is approximately less than 10% of the initial content after storage for 3 months at 25°C and 60% relative humidity.

31. Pharmaceutical product according to item 30, in which the loss of the content of the allergen is approximately less than 5% of the initial content after storage for 3 months at 25°C and 60% relative humidity.

32. Pharmaceutical product p in which the loss of the content of the allergen is approximately less than 2% of the initial content after storage for 3 months at 25°C and 60% relative humidity.

33. Pharmaceutical product according to claim 3, in which the loss of each solid dosage form is approximately less than 0.15 μg of allergen extract.

34. Pharmaceutical product p in which the loss of each solid dosage form is approximately less than 0,075 mg of allergen extract.

35. Pharmaceutical product according to clause 34, in which the loss of each solid dosage form is approximately less than 0.025 μg of allergen extract.

36. Pharmaceutical product p in which the loss of each solid dosage form is approximately less than 0.01 μg of the extract of the allergen.

37. Pharmaceutical product according to claim 4, in which the loss of the spacecraft is DOI solid dosage form is approximately less of 0.015 µg main allergen.

38. Pharmaceutical product according to clause 37, in which the loss of each solid dosage form is approximately less 0,0075 µg main allergen.

39. Pharmaceutical product according to § 38, in which the loss of each solid dosage form is approximately less than 0.0025 µg main allergen.

40. Pharmaceutical product according to § 39, in which the loss of each solid dosage form is approximately less than 0.001 µg main allergen.

41. Pharmaceutical product according to claim 1, in which the matrix is formed by sublimemovies solution containing these allergens.

42. Pharmaceutical product according to paragraph 41, in which the water content of the dosage form is between about 2% and about 8% by weight.

43. Pharmaceutical product according to any one of claims 1 to 3, in which one forms the matrix substance is fish gelatin.

44. Pharmaceutical product according to item 43, in which the ratio of fish gelatin to mannitol is from about 3:5.5 to about 6.5:3.

45. Pharmaceutical product according to item 44, in which the ratio of fish gelatin to mannitol is 4:3.

46. Pharmaceutical product according to item 44, in which the ratio of fish gelatin to mannitol is 6.5:5,5.

47. Pharmaceutical product according to item 44, in which the ratio of fish gelatin to mannitol with the hat 6,0:5,08.

48. Pharmaceutical product according to item 43, in which the solution contains from about 3 to about 6.5 wt.%./wt. fish gelatin and from about 3 to about 5.5 percent wt./wt. mannitol.

49. Pharmaceutical product p, in which the solution contains approximately 6.5% wt./wt. fish gelatin and approximately 5.5% wt./wt. mannitol.

50. Pharmaceutical product p, in which the solution contains approximately 6.0 percent wt./wt. fish gelatin and about 5,08% wt./wt. mannitol.

51. Pharmaceutical product according to any one of claims 1 to 3, in which one forms the matrix substance is pre-gelatinizing starch.

52. Pharmaceutical product according to any one of claims 1 to 42 or 44 to 50, which desintegrated in human saliva for approximately 60 C.

53. Pharmaceutical product according to paragraph 52, which desintegrated in human saliva for approximately 2 C.

54. Pharmaceutical product according to any one of claims 1 to 42 and 44 to 50, for which the allergen is selected from the group consisting of Allergy tree pollen, allergens, pollen, weeds, pollen allergens medicinal plants, ragweed allergens, cat allergens, birch allergens, allergens of grass pollen, mite allergens, chemical allergens, allergens, poisons, allergens, animal hair, dandruff allergens and food is of Llerena.

55. Pharmaceutical product according to item 54, in which the allergen is present in the form of an extract, a purified allergen, a modified allergen, or recombinant allergen or a mutant of a recombinant allergen, or any combinations thereof.

56. Pharmaceutical product according to item 54, in which the allergen is an allergen is grass pollen.

57. Pharmaceutical product p containing the main allergens of grass pollen selected from the group consisting of allergen grass group 1 allergen grass groups 2/3, allergen grass group 5 and grass allergen group 6.

58. Pharmaceutical product according to § 57, in which the allergen is present in the form of herbal extract.

59. Pharmaceutical product according to item 54, in which the allergen is an allergen mite living in the dust.

60. Pharmaceutical product p containing the main tick-borne allergen selected from the group consisting of mite group 1 allergen and mite group 2 allergen.

61. Pharmaceutical product p, in which the allergen is present in the form of an extract of mite that lives in the dust.

62. Pharmaceutical product according to item 54, in which the allergen is an allergen of ragweed.

63. Pharmaceutical product according to item 54, in which the allergen is presented in the form of an extract of ambrosia.

64. Pharmaceutical product according to item 54, which includes the main amb a 1 at the gene.

65. Pharmaceutical product according to item 54, in which the allergen is cat allergen.

66. Pharmaceutical product according to item 54, in which the allergen is presented in the form of an extract of cat allergen.

67. Pharmaceutical product according to item 54, which includes the main fel d 1 allergen.

68. Pharmaceutical product according to item 54, in which the allergen is birch allergen.

69. Pharmaceutical product according to item 54, in which the allergen is presented in the form of extract of birch allergen.

70. Pharmaceutical product according to item 54, which includes the main bet v 1 allergen.

71. Pharmaceutical product according to any one of claims 1 to 42, 44-50, and 55-70, which contains at least two different allergen.

72. Pharmaceutical product according to any one of claims 1 to 42, 44-50, and 55-70, in which the dosage form contains one or more fillers.

73. Pharmaceutical product according to item 72, which contains a filler selected from the group consisting of antacids, diluents, mucoadhesive substances, amplifier, flavouring substances, flavouring substances, substances, masking flavor, preservatives, antioxidants, surface-active substances that increase the viscosity of the substances, coloring agents, pH modifiers and sweeteners.

74. Pharmaceutical product according to any one of claims 1 to 42, 44-50, 55-70 and 73, which contains another adjuvant.

75. Pharmaceutical product p for which and juvant selected from the group consisting of aluminum salts, non-toxic bacterial fragments, cytokines, cholera toxin neutralized fractions cholera toxin, chitosan, thermolabile fragments of E. coli, neutralized fractions thermolabile fragments of E. coli, saponins, lipopolysaccharides, muramyl-dipeptide, liposomes, immune regulatory DNA sequences, and polymer microparticles lactide/glycolide.

76. Pharmaceutical product according to any one of claims 1 to 42, 44-50, and 55-70, 73 and 75, which contains another anti-allergic drug.

77. Pharmaceutical product p in which antiallergic drug is an antihistamine agent.

78. Pharmaceutical product according to claim 1 and a pharmaceutical product has a water activity of 0.4-0.5.

79. Pharmaceutical product that contains oral input solid dosage form according to claim 1, where the mentioned dosage form has a content of at least about 50% of the initial content of the allergen after storage for 3 months at 25°C and 60% relative humidity.

80. Pharmaceutical product according to any one of claims 1 to 42, 44-50, and 55-70, 73, 75, 77 or 79, and the product is chosen from the group consisting of pellets, pills, capsules and tablets in the form of a capsule.

81. Pharmaceutical product according to any one of claims 1 to 42, 44-50, and 55-70, 73, 75, 77 or 79 for the treatment is largei or relieve symptoms of Allergy to administration of the drug through the mucous membrane of the mouth.

82. Multi-dose container, which contains a lot of solid dosage forms according to any one of claims 1 to 81.

83. Multi-dose container according p, which is a blister package.

84. Multi-dose container according p, in which each of the solid dosage form contains the same amount of allergen.

85. The way of Allergy treatment and relief of Allergy symptoms, which includes an introduction through the mucous membrane of the mouth of the pharmaceutical product according to any one of claims 1 to 81.

86. The method of obtaining bestregistrycleaner non-compacted solid and stable pharmaceutical product according to claim 1, having low brittleness, containing at least one forming the matrix substance and suitable for insertion through the mucous membrane of the oral cavity, comprising an effective dose for desensitization of individuum at least one allergen, which includes stages
(a) preparing an aqueous solution containing at least one named allergen and at least one of the mentioned forms a matrix substance;
(b) introducing the solution into one or more recesses in the form;
(c) freezing and freeze-drying the completed form, using standard conditions, constant temperature and a pressure chamber, in order to obtain the solid pharmaceutical product in ka the house deepening.

87. The method according to p at which stage (b) comprises introducing the solution into the cavities in multi-layered blister sheet vinyl.

88. Set for Allergy treatment and relief of Allergy symptoms, which includes
a) many solid oral dosage forms according to claim 1 in a hermetically closed container, each of these solid oral forms is hermetically closed and fenced the place and contains an effective amount of an allergen that is appropriate for administration through the oral mucosa; and
b) each of these solid dosage forms contain the same amount of allergen.

89. Set p, in which the solid oral dosage form disintegrates within about 60 C.

90. Set p, in which the solid oral dosage form disintegrates within about 30 C.

91. Set p, in which the solid oral dosage form disintegrates within about 10 seconds

92. Set p, in which the solid oral dosage form disintegrates within about 5 C.

93. Set p, which contains more instructions for applying numerous solid dosage forms.

94. Set p, in which the dosage form is bistrotdepierrerue drug f the RMU.

95. Set p, in which each of the solid dosage forms are placed in individual hermetically sealed blisters compound in the blister pack.

96. Set p, in which the solid dosage forms contain gelatine.

97. Set p, in which the matrix forming agent is a fish gelatin.

98. Set according to any one of p-97, in which an effective amount of allergen is approximately 2.5 μg - about 3.75 mg of extract/solid dosage form.

99. The use of solid dosage forms, which are characterized in any one of claims 1 to 42, 44-50, and 55-70, 73, 75, 77 or 79 for the treatment of allergies or relieve symptoms of Allergy to the introduction of the dosage form through the oral mucosa.



 

Same patents:

FIELD: medicine.

SUBSTANCE: according to the invention, a matrix tablet contains trimetazidine, polymer of methacrylic acid, wax and adjuvants. Montanic glycolic wax is used preferentially. A core tablets are film coated.

EFFECT: tablet provides prolongation of antiischemic effect to 8 or 12 hours and intake of preparation once or twice a day.

16 cl, 1 dwg, 1 tbl, 7 ex

FIELD: medicine.

SUBSTANCE: present invention refers to a delivery system for pharmaceutical compositions, partially based on ionic interaction to regulate and facilitate release of therapeutic agents, and concerns a bioadhesive pharmaceutical composition in the form of the gel, not containing an oil phase, with prolonged controlled release, containing an ionic therapeutic agent and ionic polymer wherein polymer is ionised enough to release a therapeutic agent in a controlled way throughout a long period of time, and a composition does not require an emulsion system to be introduced.

EFFECT: composition provides controlled release of a therapeutic agent.

10 cl, 6 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: composition contains a pharmacological agent, water-soluble polymer and a fatty base. The pharmacological agent is chosen from a group, containing diclofenac, acetylsalicylic acid, paracetamol, ibuprofen, ketorolac, pentoxifeylline and ciprofloxacin. The water-soluble polymer is chosen from a group, containing hydroxypropylmethicellulose, polyvinylpyrrolidone, egg white, sodium caseinate, milk protein, guar gum, sodium alginate, pectin, chitosan acetate, polygalactomannan, dextran or their mixture. The fatty base relates to oils consumed by human beings, which melt at temperature between 30 and 36°C and chosen from a group containing: cocoa bean oil, coconut oil, milk fat, pork fat, hydrofat or their mixture. The said pharmacological agent and water-soluble polymer are contained in the composition in form of a non-covalent complex.

EFFECT: obtaining a dosage form with intense prolonged effect.

3 cl, 3 dwg, 1 tbl, 1 ex

FIELD: medicine; pharmaceutics.

SUBSTANCE: invention concerns a matrix tablet with a basis for the prolonged trimetazidine or its pharmaceutically comprehensible salt release, (rather, trimetazidine dihydrochloride), possessing membrane stabilising, cytoprotective, antihypoxant and antioxidatic activity containing the combination of hydroxypropyl cellulose and copovidone, at their quantitative parity 20.0-24.7 wt % and 1.3-8.0 wt % in quality of a matrix forming component, way of its reception, way of treatment or prevention of conditions at which introduction of antioxidants is necessary, antihypoxants, cytoprotectors and membrane stabilisers. The offered invention provides optimum quantitative and qualitative structure of components for manufacturing of solid peroral medicinal forms of trimetazidine or its pharmaceutically comprehensible salt of the prolonged action, not rendering allergenic and toxic action, providing gradual and prolonged liberation of the agent during the long period of time.

EFFECT: stable maintenance of effective concentration of trimetazidine in a blood plasma throughout the long period of time.

16 cl, 1 ex, 1 tbl, 1 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns medicine area, namely to peroral medicinal forms on a basis of biphosphonates, containing safe and effective quantity of the pharmaceutical composition containing biphosphonate, chelated agent and an agent for effective delivery of a pharmaceutical composition in the bottom gastroenteric tract of a mammal, and also pharmaceutically active biphosphonate absorption together with nutrition or drinks or without them. The present invention essentially reduces interaction between biphosphonates and nutrition or a drink, which (interaction) leads to that active biphosphonate component is not accessible to absorption. The final peroral medicinal form can be accepted both with food, and without it. Further, the present invention influences delivery biphosphonate and chelated agent in a bottom of GI tract, essentially reducing irritation of top of the GI tract, bound with biphosphonate therapy.

EFFECT: maintenance of fuller observance with the patient of a regimen biphosphonate therapy.

23 cl, 20 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention concerns area of medical products, in particular to structure for oral tablets with the modified release, containing fine gliclazide for depression of level of a glucose in blood with defined granulat metric structure, and also the agent modifying liberation, for gliclazide release control; and fine gliclazide for depression of level of a glucose in blood has certain profiles of dissolution in the cleared water. Besides the invention concerns the way of reception of the specified structure.

EFFECT: decrease of level of glucose in the blood during long period of time.

8 cl, 3 dwg, 9 tbl, 8 ex

Solid preparation // 2359661

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns pharmaceutics and medicine and concerns a solid medical product for treatment of diabetes containing a layer, including Pioglitazone, and the layer including Glimepiridum and Polysorbate 80. The agent possesses good indicators of solubility.

EFFECT: development of a preparation with good indicators of solubility.

2 cl, 2 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of medicine and pharmaceutics and concerns angiatherosclerotic composition including intestine-soluble coating and core, which contains 1-(N-(2-(diethylamino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)tio-5,6-trimethylenepyrimidin-4-one and one or several additives, selected from loosing agent, thinner and binding agent.

EFFECT: elaboration of composition with high bioavailability.

10 cl, 9 tbl, 8 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly to pharmacy. There is disclosed new preparation. Controlled-release Proxodolol is prepared effectively and conveniently with applying one or more mixed swelling or gelling components, an active component and pharmaceutically acceptable filler. It is preferential to apply a tableted preparation containing Proxodolol dosed 120 mg, hypromellose and pharmaceutically acceptable fillers, e.g. microcrystalline cellulose, calcium stearate and aerosil. New pharmaceutical forms with a suitable Proxodolol release profile allow reducing number of daily dosages while concentration of active component is constant within a therapeutic dose.

EFFECT: stable kinetic indicators of active material delivery.

8 cl, 5 ex, 5 tbl

FIELD: medicine.

SUBSTANCE: combined medical form with controlled release for peroral introduction, which contains a) part with controlled release, which contains metformin or its pharmacologically acceptable salt as active ingredient, and combination of polyethylenoxide and natural pitch as carrier for controlled release and b) part with quick release, which contains anti-diabetic medication based on sulfonylurea as active ingredient, applied on part with controlled release, intended for diabetes treatment.

EFFECT: possibility to support effective concentration of medications in blood at constant level.

19 cl, 21 ex, 18 tbl

FIELD: medicine.

SUBSTANCE: pharmaceutical composition for making tableted dosage form with modified release for oral administration of calcium channel blocker-felodipine contains felodipine or its pharmaceutically acceptable salt, a carrier for modified release and a hydration gel accelerator. The carrier for modified release is a salt of alginic acid with an alkali metal. The hydration gel accelerator is hydroxypropyl methylcellulose.

EFFECT: provision for relatively fast (during several hours) release of felodipine, with simultaneous prolonged retention of its concentration in blood plasma at a stable high level, and is characterised by low cost of production.

20 cl, 1 dwg, 2 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: claimed invention relates to chemical-pharmaceutical industry and concerns auxiliary binding substances for manufacturing drop-shaped tablets and to preparation of drop-shaped tablets. Auxiliary binding substances according to claimed invention are selected from group which consists of monosaccharide, oligosaccharide, polysaccharide, sugar ester, sugar of alcohol structure, alpha-hydroxy acid, higher fatty acid derivative, higher aliphatic alcohol, polyol, urea and poly(ethyleneoxide) derivative.

EFFECT: claimed invention reduces toxicity caused by polyethylene glycol, improves drop-shaped tablet quality and accelerates development of drop-shaped tablets.

20 cl, 68 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: pharmaceutical composition is intended for cancer treatment. As active ingredient composition contains suberoylanilide-hydroxamic acid (SAHA) or its pharmaceutically acceptable salt or hydrate. Invention also relates to method of obtaining crystalline active ingredient SAHA.

EFFECT: definite profile of SAHA particles distribution according to their size, which in its turn results in improved profile of solubility in vitro and optimal SAHA bioavailability.

27 cl, 16 dwg, 22 tbl, 17 ex

FIELD: medicine.

SUBSTANCE: invention concerns area of pharmacology and concerns the method of compositions creation for delivery of medical preparations. The method includes preparation of a polymeric basis with 75-98% thixotropy, thus in the course of an admixture withstanding in 2 hours after medicinal preparation introduction an assay sampling in volume of 100 g and loading researches are carried out. For this purpose the assay is drifted through a tube in diameter of 0.6-1.0 cm, length 10-14 cm, at a load of 4.8-10.8 kg, and if the assay passes through the tube during 4-140 sec, then the process of composition creation is considered to be finished and this composition is used for medical preparation delivery.

EFFECT: invention provides address delivery of medical preparations.

9 cl, 5 ex

FIELD: medicine.

SUBSTANCE: invention relates to field of medicine. Claimed is composition with hyaluronic acid (HA), which includes gel particles of bound water-insoluble hydrated HA. HA includes bindings, represented with the following structural formula: HK'-U-R2-U-TK'. Where each group HA' represents the same or other molecule of bound HA'; each U independently represents optionally substituted 0-acylisourea or N-acylurea; and R2 represents optionally substituted alkyl, alkenyl, alkinyl, alkoxy, cycloalkyl, cycloalkenyl, cycloalkinyl, aryl, heteroaryl, heterocyclic radical, cycloaliphatic alkyl, aralkyl, heteroaralkyl or heterocyclolalkyl. Also claimed is method of developing tissues in individual, including introduction of needle into individual in place where development of tissues is necessary, needle is connected to syringe filled with composition with HA, and applying force to syringe in order to supply composition with HA to individual. Method of obtaining composition with HA includes formation of water-insoluble dehydrated particles of bound HA, separating insoluble in water particles by their average diameter, selection of subset of particles by average diameter and hydration of subset of dehydrated particles by means of physiologically compatible water solution. Other method of obtaining composition with bound HA includes binding precursor of bound HA by means of bis-carbodiimide in presence of pH buffer and dehydration of bound HA. Also included is method of developing tissues in individual that needs tissue development. Method of stabilisation of bound HA includes hydration of water-insoluble dehydrated bound HA by means of physiologically compatible water solution which includes local anesthetic, so that value of elasticity module G' for stabilised composition constitutes not less than approximately 110% from value G' for non-stabilised composition.

EFFECT: claimed composition of hyaluronic acid and method of preparation and application of HA composition are efficient for development of tissue and/or drug delivery.

27 cl, 22 ex, 2 tbl, 7 dwg

FIELD: medicine; pharmacology.

SUBSTANCE: composition contains, essentially anhydrous ordered (adhesive) mixture of, at least, one pharmaceutically active agent in the form of microparticles linked to surface of carrier particles which are essentially greater than those of the active agent or agents, and, essentially are water insoluble or poor soluble, in a combination with the agent enabling bioadhesion and/mucoadhesion, linked to surface of specified carrier particles. The composition, mainly, is used for sublingual or intranasal introduction. Besides, the invention refers to method of composition preparation.

EFFECT: improved bioadhesive properties, fast release of active substance.

31 cl, 1 dwg, 1 tbl, 1 ex

FIELD: medicine; pharmacology.

SUBSTANCE: semifirm pharmaceutical compositions for local application include ascomycene in solution of carrier including three-componental admixture of dissolvents, component not less than 40% wt from lump of composition and consisting from: i) C3-8-alkanol and-or C1-8-alkandiol; ii) fat alcohol iii) additional dissolvents chosen from the family, containing:) alkyl ether of alkancarboxylic acid and-or alkyl ether alkandincarboxylic acid and-or a hydrophylic additional component and-or a triglyceride. Besides, the invention concerns application of the specified composition and the method of treatment of inflammatory and hyperproliferative diseases of skin and dermal implications of immunologically mediated diseases.

EFFECT: improvement of penetration of active substance.

9 cl, 7 tbl, 26 ex

FIELD: medicine; pharmacology.

SUBSTANCE: composition contains complex of platinum as active substance, with, at least, one pharmaceutically comprehensible excipient, differing that it is formed from granulate with in the size of particles less than 0.5 mm, obtained by wet granulation of admixtures of a complex of the tetravalent platinum wetted by water, at least, one neutral saccharide and, at least, of one native and-or modified polysaccharide, unessentially, contains in capsule or bag or, unessentially, is pressed in the tablet form while the granulates surface, capsules or tablets, unessentially, is covered by layer, at least, one pharmaceutically comprehensible substance providing enteric dissolution of active substance only in intestine, and-or, at least, one pharmaceutically comprehensible substance.

EFFECT: controllable liberation of active substance.

18 cl, 28 ex

FIELD: medicine; pharmacology.

SUBSTANCE: pharmaceutical composition includes an anthelminthic agent chosen from the group, consisting of macroleads, benzimidazoles, isoquinolones, pyrantel or their mixes, and the first inert material, masking taste. The inert material has porous structure with an internal surface approximately of 500-1500 m2/g and the surface area according to VET is approximately 5000 m2/g. As an inert material, usually use charcoal.

EFFECT: improved masking of taste and the prolonged liberation of the anthelminthic agent.

16 cl, 1 dwg

FIELD: medicine; pharmacology.

SUBSTANCE: composition includes effective amount of carbamazepine as active ingredient, and carbomer 71G, microcrystalline cellulose, sodium carboxymethylstarch, aerosol, and stearate salt as auxiliary ingredients. The composition is manufactured by direct pressing method, preferably in form of tablets.

EFFECT: composition stability during storage period, release profile reproducibility of active substance, satisfactory pharmacokinetic characteristics, and high strength of the tablets.

5 cl, 1 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: invention relates to novel emulsion of "oil in water" type intended for parenteral introduction. Emulsion contains as active ingredient badly soluble in water compound with anti-tumor activity of taxans class, for example paclitaxel or docetaxel in concentration from 1 to 30 mg in 1 ml of emulsion. Emulsion also contains lecithin, effective quantity of antioxidant, stabiliser of emulsion, dimethylsulphoxide as co-solvent of active ingredient and lactide or glycolide co-polymer as active ingredient stabiliser. Emulsion contains particles with size less than 100 nm in quantity not less than 80%. Emulsion by invention is stable when diluted with infusion solutions.

EFFECT: invention removes defects, connected with presence in applied in therapy of tumor diseases compositions of co-solvents, which have toxic effect on human organism, as well as with instability of known emulsions in dilution with infusion solvents.

29 cl, 6 dwg, 1 tbl, 7 ex

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