Matrix providing prolonged, invariant, and independent releasing of active substances

FIELD: pharmaceutical industry.

SUBSTANCE: invention relates to composition containing at least two active ingredients, opioid analgesic, and opioid agonist in non-swelling diffusive matrix. Releasing characteristics are defined by matrix made of ethylcellulose and at least one fatty alcohol. Also disclosed is pharmaceutical preparation containing 10-150 mg of oxycodone and 1-50 mg of naloxone in standard dose.

EFFECT: composition of long storage time with prolonged invariant and independent releasing of substances.

17 cl, 14 dwg, 16 ex, 19 tbl

 

The invention relates to stable storage to a pharmaceutical preparation containing at least one pharmaceutically active compound in almost no swellable diffusion matrix, and the release of compounds from the matrix is extended, invariant and, if there are multiple connections, independent. As for its main release characteristics, the matrix composition is mainly ethylcellulose and at least one fatty alcohol.

The invention also relates to a method for producing stable during storage of pharmaceutical preparations containing at least one pharmaceutically active compound in almost no swellable diffusion matrix, and the release of at least one compound from the matrix is extended, invariant and, if there are multiple connections, also independent.

Pharmaceutical acting drugs play a major role in the creation of improved medicines. The sense of creating all of the sustained-release preparations is to provide a more prolonged pharmacological action after administration of a drug, rather than a pharmacological effect observed after administration dosage forms quick action is imposed. The pharmaceutical use of long-acting drugs, containing relatively large amounts of pharmaceutically active compounds, in which the release of the connection is controlled and regulated for a longer period of time (usually 2-16 hours), ensures that the patient should be less likely to give the drug, which leads to higher flexibility (the degree of agreement with the regime) patients.

Longer selection (release) and concomitant prolonged action of the active compounds, guaranteed pharmaceutical preparations with prolonged action, gives, in addition, many advantages in the treatment that cannot be achieved by appropriate drugs instantaneous. Treatment with the use of pharmaceutical preparations with prolonged action may continue, for example, at night, there is no need to disturb the sleep of the patient. This is important, for example, in the treatment of patients with epilepsy, so it is possible to prevent nocturnal attacks. To some extent, in patients suffering from chronic pain, not disturbed sleep.

With medico-pharmacological point of view one of the advantages of long-acting drugs is completely uniform concentration of active is the first compound in the blood, that gives prolonged action and reduced side effects. Reduce side effects plays a crucial role, for example, when using opioids in the treatment of pain. Side effects caused by opioids, create, among other things, the danger of addiction. Because of the addictive potential of active compound is determined not by the Union, but rather the method of application and the resulting pharmaco-dynamics (for example, the speed with which the active compound penetrates into the brain), prolonged isolation of opioid analgesic may be reduced addictive potential of these active compounds (Nolte, T.: STK-Zeitschrift fur angewandte Scmerztherapie, 2001, Vol.2).

As a long-acting drugs allow you to create a uniformly high concentration of active substances in the blood, increases the bioavailability of active compounds. Bioavailability of active compounds is determined by many factors. Such factors include the concentration of active compounds in appropriate biological fluid (e.g. blood), the absorbability of the active compounds membranes (for example, when reabsorption in the gastrointestinal tract) and the availability of active connections in the right place tissue.

In order to be absorbed, for example, in the intestine, the active compound should be present in the solution. Time, traboulsee is for to view the active compound in the proportions present in the standard dose of a pharmaceutical product, dissolved in an appropriate physiological fluids, is the time of dissolution, and time allocation (release) or release rate. The time of dissolution of the active compound is determined by the test method in standardized conditions as a proportion of the active substance is released from the standard dose for a specific time. The physiological fluid in which determine the time of dissolution of the active substance may be, for example, fluid from the gastrointestinal tract. In modern technology there are many known methods of test for measuring the time of dissolution of the pharmaceutical compositions (and thus speeds the selection of active compounds), and these testing methods are widely described in an official Pharmacopoeia.

Among the various factors influencing the time of dissolution of the pharmaceutical compositions, and, consequently, on the rate of release of active compounds, the surface area of the pharmaceutical compositions available for solvent environment (environment with solvent) for dissolving, the pH of the solvent environment for dissolution, solubility of the active compound in the solvent medium for the dissolution and saturation concentration of dissolved materials in rastvorjajus the environment for dissolution.

Despite the many factors that affect the dissolution of the active compound in the solvent environment, as well as on the absorption of active compounds, establish a strict correlation between in vitro time of dissolution, specific to the pharmaceutical product, and in vivo bioavailability of the active compounds. This correlation is so clearly established that the time of dissolution (release rate of active compound) is considered as a generally accepted criterion bioavailability of the active compounds a pharmaceutical preparation. Given this correlation, it is clear that the allocation rate determined for the active connection of a pharmaceutical product is one of the fundamental characteristics that should be taken into account when assessing the long-acting drugs.

From the previous known in the art various methods (approaches), which allow to obtain sustained-release preparations. These methods (approaches)that have a common, namely the active compound, together with additives, getting decorated objects, such as tablets or pills, this Supplement creates a barrier that slows the release or dissolution of the active compound. Depending on the nature of the barriers that slow down the release, you can divide the methods of prolonged action. Beings who have, for example, osmotic systems, deceleration is achieved by coating, or systems in which the active compounds are applied to the wax, polymethacrylates, gel-forming substance or silicic acid. In addition, there are the so-called "matrix" form, in the form of matrices, which are of fundamental importance in the preparation of long-acting drugs. The matrix denotes the decorated object containing the active connection associated with the additives that are, as far as possible, inert. Depending on the type of matrix it is possible to distinguish between swelling and kinabuhayan matrix. In addition, the matrix will vary depending on what is released if the active connection is due to the net diffusion or by erosion of the matrix (U.Schöffling, Arzneiformenlehre, 1998, 3rdedition, Deutscher Apoteker-Verlag, Stuttgart).

Additives used for the preparation of pharmaceutical preparations with prolonged action, often cause problems with the stability of a pharmaceutical product after prolonged storage. For example, it is shown that the waxes are changing, so should take strong precautions even while cooking to prevent changes during storage. If to slow the release film used dormancy the eve ENT, consisting of polymers obtained from aqueous dispersions, these pharmaceutical drugs are also often create problems related to stability during storage.

Known pharmaceutical preparations with prolonged action with the so-called controlled (regulated) by the release of pharmaceutically active compounds, i.e. the release of the active compounds is not only prolonged, but in addition, the rate of release can be increased to predeterminable values. Depending on what polymers (hydroxyethylcellulose, polymethacrylates or, for example, alkylsilanes) is used to obtain, for example, immobilized on the matrix pharmaceutical preparations with prolonged action controlled release can vary the properties of the respective pharmaceutically active compounds in the release, and the properties of the active compounds is often difficult to predict.

As a rule, should ensure that the pharmaceutical preparations of this pharmaceutical composition is released the corresponding connection is always reproducible equal speeds or release profiles, even if the composition contains various absolute number of active connections. However, due to problems with sustainability (stability),caused by components, responsible for the prolonged release, it is not guaranteed.

There are a large number of long-acting drugs with different therapeutic action, which often contain only one active connection. Drug Oxygesic®, which is used in therapy for the treatment of pain, for example, contains oxycodone as the sole analgesic active ingredient. The drug Kapanol®, which is also used to treat pain, contains martinslife as analgesic active connection.

Because prolonged use of opioid analgesics, such as oxycodone, may be accompanied by the appearance (development) side effects, such as weakening of breath and persistent constipation may occur the need for simultaneous treatment of patients with opioid antagonists that specifically counteract caused by opioid side effects. If patients seeking pain relief, be treated with medicines containing opioid analgesic, to counter the above side effects may be desirable concomitant treatment with drugs containing antagonists, such as naltrexone or naloxone. If the containing opioid drug is a drug with a prolonged action, the drug provided the antagonist, must also provide a prolonged release, because otherwise it is impossible to effectively suppress the occurrence of side effects. However, the long-acting drugs such as naloxone, are not available.

Therefore, in the treatment of various symptoms there is a General strategy to counteract the side effects caused by the active connection with the simultaneous use of another compound that selectively reduces these side effects. If, for example, opioid analgesics used in the treatment of pain, in addition to the risk already mentioned the development of dependence and addiction can manifest side effects such as persistent constipation and easing breathing. So I made various attempts to eliminate or at least greatly reduce addictive potential and the potential of addiction to opioid analgesics, as well as their side effects, with simultaneous reception of antagonists, which resist the action of opioid analgesic.

Due to the significant benefits that have such a combination of drugs, and due to the above-mentioned General advantages of pharmaceutical preparations with prolonged action, there is an urgent need for such combined preparations with prolonged action. Combined PR the preparations with prolonged action should the ideal way to combine positive Energeticheskie effects of various active compounds prolonged release and, therefore, increase the effective period of the action.

One example of such a combined drug that releases in a long time, multiple connections, is Valoron®Gödecke, which contains tilidin as analgesic active connections and naloxone as an antagonist.

However, one problem that is often encountered in combined preparations is that the active compounds of different chemical structure and different physical properties must be combined into a single matrix. This combination usually gives different release profiles for both compounds. However, from a medical point of view may be highly desirable for the release of both compounds with the same profiles. In addition, it may be preferable that both compounds were released from the same matrix, as in this case can be obtained, for example, tablets that can be split. Such pills are applicable for individual reception, and the production process of such drugs can be significantly simplified. Another aspect is that when there are several compounds with different structures, the stability of these compounds is of deposits in the matrix during prolonged storage may vary. In addition, changes in the number of single connection in the combined drugs may unpredictably change the profile of the release of other compounds that result in significant cost in the production of preparations containing different amounts of the active compounds, as it is impossible to conclude about the behavior of one drug when judged on the basis of the properties with the release of another drug.

Typically, medications should be prepared so that the active compounds were stable in standard storage conditions as possible for a long time. Medications also should be prepared so that the expected release profiles of the active compounds did not change during prolonged storage.

You should also ensure that the release profile of one of the active compounds of this drug prolonged action did not change depending on the number of active connections. This applies both to the case in the pharmaceutical preparation has a single connection, and to the case when there are multiple connections.

In addition (in the case of the combination of active compounds), the release profile of each single connection, if necessary, must SEL is collected. Measurements that are conducted to achieve this goal, should not prevent the release profiles of additional active compounds or even to hinder them, for example, in the case of a combination of different active compounds selected if necessary. Therefore, there should be interdependence of release profiles.

For various applications in therapy there is an urgent need in the combined drugs. In particular, requires a combination of drugs to treat pain, consisting of opioid analgesics and related antagonists, and corresponding pharmaceutical preparations should release both connections for a long time and also have the above properties. Drugs in the matrix, which provide prolonged action of active compounds, in General, and opioid analgesics and antagonists, in particular, and which have the above properties, in the previous prior art is not known.

Patent application Germany DE 4325465 A1 relates to the treatment of side effects in the treatment of pain using medication, consisting of opioid agonist and antagonist. Characteristic of this application is that the antagonist may be released not extended way, whereas the agonist must have a prolonged action.

Between Hrodna patent application WO 99/32120 also applies to the drug, containing the opioid analgesic and antagonist. According to this application, both of these compounds must be released prolonged way. However, the storage stability and the mutual dependence of the release profiles of the compounds is not the subject of the invention in this application.

The aforementioned drug Valoron®is a combination of Tilidine/naloxone. According to the manufacturer of this drug, from which both the active compounds are released prolongirovanne. Applied matrix contains relevant part of swelling in water of the material (hydroxypropylmethylcellulose (receiver array)) and, therefore, should be seen as swelling (and possibly partially erosion) diffusion matrix. The disadvantage of this famous recipe is that Tilidine and naloxone, with the same mass ratio, but with different absolute values give different release profiles, if the release is measured at certain pH values. Speed of release of the agonist and antagonist are not independent from each other, which is probably due to the formulation of prolonged action. Therefore, the physician must conduct intensive experiments to determine the titer for each individual patient, if he wants to increase the dose, even if it is not ineet mass ratio tilidin: Maxolon, since he cannot be sure that the release profiles of both components remain constant. Therefore, the interval therapeutically applicable quantities of analgesic, suitable for doctor, is limited.

One of the purposes of the present invention is to provide formulations for pharmaceutical products, which guarantee that the active compounds are released from the sustained release formulations way that is stable during prolonged storage and release a single connection does not change, even when using different number of active connections. Another objective of the invention is to provide formulations of pharmaceutical preparations which exhibit the above properties and in which there is mutual dependence of the release profiles of active connections.

Another objective of the present invention is to provide methods for producing pharmaceutical preparations containing at least one pharmaceutically active compound and from which connections are released extended, reproducibly invariant and, in the case of presence of several compounds in an independent manner. Such drugs should remain stable even on prolonged storage.

The specific objective of the present invention to provide compositions for pharmaceutical whom such drugs, which contain the opioid antagonist naloxone, in which the active connection is stable during prolonged storage and is released from the product of prolonged and reproducibly invariant way. Drugs that meet this requirement are not known in the previous art.

An additional objective of the present invention is the preparation of compositions for pharmaceutical preparations for the treatment of pain, containing at least one opioid analgesic and at least one antagonist, which is opposite to the effect of opioid analgesic (opposition), and the composition is stable during long storage, and active compounds are released from the drug independently from each other prolongirovaniem and reproducibly invariant way.

In accordance with the invention, these objectives are achieved by creating a pharmaceutical formulation containing at least one pharmaceutically active compound in almost no swellable diffusion matrix, and the matrix is to be made, depending on the main characteristics of the release, based on ethyl cellulose and at least one fatty alcohol.

Unexpectedly, it was found that only the formulations containing little or no swelling of the diffusion matrix based on ethyl cellulose and, what about the least one fatty alcohol, provide a prolonged, invariant and, if there are several active substances, the independent release of the active compounds.

The drug in the matrix according to the invention, which is stable during storage for a long time, always ensures that the active connection is always released in predeterminable percentage and that the speed of release do not affect each other. In combined preparations which contain, for example, opioid analgesics and related antagonists prevents incorrect behavior of drugs, which suggests that the agonist can be selectively removed from the recipe.

Part of the preparation according to this invention blocks the selective extraction of the agonist of the drug without the right amount of antagonist, regardless of what the absolute and relative number of agonist and antagonist is selected. In addition, these drugs reduce the side effects commonly seen with use of opioids. Since the active compounds are released from the same matrix, it is possible a simpler and more effective way of obtaining. This also applies for combined preparations containing other compounds than opioid analgesics and their antagonists. The AOC is e, the formulation of the preparation according to the invention ensures that when identical relative amounts of the active compounds give the same release profiles regardless of the available absolute number. Such independent behavior when released allows the physician to operate in a wide range of applied absolute quantities of active compounds, and the optimal ratio of compounds (for example, the ratio of the opioid agonist/antagonist) is known. Thus, you can simply adjust the dosage for each individual patient, or gradually increasing the dose, or, if necessary, gradually increasing the dosage. This ability to adjust the dosage for the individual patient is extremely convenient from a medical point of view, since it allows to improve the regimen.

Formulations according to the invention also allow you to obtain pharmaceutical preparations which release the active compounds of different structures with the same profiles.

As predeterminable the release of the active compounds of the formulations according to the invention does not change regardless of the number and the number of connections and comes from the same matrix, when you have a combination of active compounds, drugs with different amounts of active soedineniya be obtained without significant technical difficulties and can get the appropriate drugs for a variety of therapeutically relevant fields.

Characteristic features of the present invention is prolonged, invariant and, if there are several active compounds, the independent release of the active compounds from non-swelling (at least to the extent that it is relevant for release) diffusion matrix, and the matrix is determined in relation to the main characteristics of the release ethylcellulose and at least one fatty alcohol and the active compounds, stable during prolonged storage.

According to the present invention "prolonged" or "controlled prolonged release (the selection effect)or the deceleration means that the pharmaceutically active substances are released from medical treatment for a longer time than in the case of known drugs immediate action. Preferably, the release occurred within two to twenty-four hours, two to twenty hours, particularly preferably within two to sixteen hours, or two or twelve hours, with specifications must comply with legal requirements.

In the context of the present invention "prolonged action" does not mean that the active compounds are released from the formulation or medication depending the on pH. According to the invention, the term "prolonged action (release)" refers to the release of the active compounds from the drug for an extended period of time. It does not imply controlled release in a certain place; therefore, it does not mean that the active compounds are released only in the stomach or only in the intestine. Accordingly, the release of the active compounds of the formulations according to the invention, preferably, occurs independently of the pH.

(Of course, the pH - dependent release in a specific location can be achieved, for example, using Intercollege cover the drug, although in this case, apparently, is not favorable.)

According to the invention independent release (action)" means that in the presence of at least two active compounds of the absolute change amounts of the same compounds do not affect the release profiles of other compounds, thus, the profiles of other compounds do not change. For formulations according to the invention, this characteristic is independent of the release is independent of pH, which determines the release, or from the process of obtaining. PH-independence is particularly applicable to the interval acidic pH values, i.e. pH<7. Profile releases (or the behavior, features and advantages of the ICA, property release) is defined as the change in the release of active compound from the formulation over time, and the released amount of each active compound is expressed as a percentage of the total number of active connections. The release profile define the known testing methods.

Specifically this means that, for example, the release profile of oxycodone observed for the combination oxycodone/naloxone, contains 12 milligrams of oxycodone and 4 milligrams of naloxone, is not changed if the corresponding drug of the same formulation contains 12 milligrams of oxycodone, but 6 milligrams of naloxone.

Feature independent release, preferably, refers to a situation when comparing the release profiles of the drugs actually (mostly) equal composition. Drugs are almost equal composition contain different amounts of active compounds, but remain essentially the same in respect of the components of the composition, which practically affect the characteristics of the release.

If, for example, compare the above two drugs (the first product contains 12 mg of oxycodone and 4 mg naloxone, and the second product contains 12 mg of oxycodone, and 6 mg of naloxone), both drugs, provided that they have the same total weight, will give the same profile vysvobojdenie of oxycodone and naloxone, if the difference in the number of naloxone to replace a component in the formulation, which, as a rule, does not affect the features (characteristics) of a release.

Specialist in the art understands that if the difference in the number of active connections in the two drugs to replace material that has a significant impact on the characteristics of the release composition, such as ethylcellulose or fatty alcohol, you may experience differences in the features (characteristics) of the release. Therefore, the characteristics of the independent release is applied to the compositions, which contain different amounts of active compounds, but are identical or at least highly similar in terms of components that can significantly affect the characteristics of the release properties when the release).

According to the invention "variantnye features of release" or "invariant profile release" is defined in such a way that the percentage of the absolute amount of each active compound released per unit of time, does not change much and remains almost constant (and, therefore, does not practically change, if the absolute amount of change. Pretty (almost) constant percentage means the percentage released is the time unit of the substance deviates from the mean by no more than 20%, preferably, not more than 15% and, most preferably, not more than 10%. The average value calculated from the six measurements of the release profile. Of course, the amount released per unit of time, must meet legal and regulatory requirements.

Specifically, this means that in the case of the combination oxycodone/naloxone containing 12 mg of oxycodone and 4 mg naloxone, during the first 4 hours released 25% of oxycodone and 20% of naloxone. If, instead, the combination oxycodone/naloxone contains 24 mg of oxycodone and 8 mg naloxone, during the first 4 hours is also released 25% of oxycodone and 20% of naloxone. In both cases, the deviation will not exceed 20% from the average value (which in this case is 25% of oxycodone and 20% of naloxone).

As outlined about the features of the independent release feature (feature) invariant release refers to a situation when compared to the drugs actually (mostly) the same composition. These drugs differ in the number of active substances, but have the same or at least highly similar components of the drug, influencing the release. Typically, the difference in the number of active connections replace a number of pharmaceutically inert excipient that PR is chicosci does not affect the features (characteristics) of the release of the drug. Such pharmaceutical excipients may be lactose, which is a typical filler in pharmaceutical preparations. Specialist in the art knows that the invariant release may not relate to drugs, in which the difference in the number of active connections replace substances of which it is known that they have a significant impact on the characteristics of the release composition, such as ethylcellulose or fatty alcohol

In the "Examples" section shows that if a product contains 20 mg of oxycodone and 1 mg of naloxone or 20 mg of oxycodone and 10 mg of naloxone, with the difference in the number of naloxone replaced by lactose, the two drugs are identical weights give the same release profiles, so that they are extended, invariant and independent behavior.

According to the invention, the expression "stable storage" or "stability during storage" means storage under standard conditions (at least two years at room temperature and normal humidity), the deviation amounts of the active compounds in medical drug from initial quantities not exceeding the values given in the description or guides usual Pharmacopoeia. According to the invention, the storage stability also means that the product obtained according to the invention can keep the change in standard conditions (60% relative humidity, 25° (C) as required for market acceptance.

According to the invention is stable upon storage" or "stable over time" also means that after storage in standard conditions, the release profiles of the active compounds are the same as if these drugs are used immediately, without any storage. According to the invention acceptable fluctuations release profile characterized by the fact that the amount released per unit time differs by not more than 20%, preferably not more than 15%, and especially preferably not more than 10% of the mean value. The average value is calculated from the six measurements of the profile of the release.

The term "stable storage" refers to the active compound and other components included in the formula according to the invention, and, consequently, to the formulation as a whole.

Preferably, release of the active compounds of formulas prolonged action determine the basket method (Basket) in accordance with USP at pH 1.2 or pH 6.5 using HPLC.

Stability (stability) during storage, preferably, define the basket method (Basket) in accordance with USP at pH 1.2 using HPLC.

According to the invention, the term "formulation, composition refers to the composition of pharmaceutically active substances with additives (excipients is), promote optimum release, distribution and creation of activity of active compounds for use in appropriate order.

According to the invention the expression "no swelling" and "virtually no swelling" of the diffusion matrix indicate the drug in the matrix, in which the swelling of the matrix has no effect (or, at least, are not affected in the relevant extent) the release of the active compounds (especially in physiological fluids relevant sites to target in the body of the patient).

According to the invention, the term "virtually no swelling" of the diffusion matrix also applies to the matrix, the volume of which increased by about 300%, preferably about 200%, more preferably about 100%, about 75% or about 50%, even more preferably about 30% or about 20% and most preferably about 15%, about 10%, about 5% or about 1% (and especially in physiological fluids relevant sites to target in the body of the patient).

Now unexpectedly found that the formulations of drugs with virtually no swelling diffusion matrices make it possible prolonged, invariant and, in cases where there are multiple connections, independent release Akti is different compounds, if the diffusion matrix contains ethylcellulose as a substance that forms the matrix is a framework, and, in addition, the main features of the release are determined by ethylcellulose and/or at least one fatty alcohol. In addition, these formulations are characterized by good storage stability. At the present level of knowledge recipe mainly with such diffusion matrices make possible the release of the active compounds by the above method according to the invention. Formulations with (almost) swellable diffusion matrix or erosion of the matrix is currently not considered suitable for this purpose.

Consequently, the swelling in water of a substance and especially a swelling in water of the polymers, as a rule, cannot be used as carisoorodol substances upon receipt of the matrices for the compositions according to the present invention. In particular, such conventional patriciabrasel polymers like polyvinylpyrrolidone, hydroxypropylcellulose, hypromellose, hydroxyethylcellulose, hydroxymethylcellulose, poly(vinyl alcohols), alginates, the hydrated hydroxyethylcellulose and simple broadcast hydroxypropylmethylcellulose currently considered unsuitable to obtain formulations according to this invention.

Carisoorodol substances, to the which can form not swellable diffusion matrix, can be used to obtain preparations according to this invention, if they provide particular release of the active substance in accordance with this invention, ie, prolonged, invariant and, in the case of multiple components, independent release, and the storage stability of the preparation. Water-insoluble polymers that are typically used to obtain pharmaceutical preparations with prolonged action on the matrix, also cannot be directly applied to obtain the formulations according to this invention. Normal carisoorodol substances, such as copolymers of acrylic and methacrylic acid, copolymers of methyl methacrylate, copolymers of ethoxyethylacetate, copolymers of cyanoacrylate, aminoalkylsilane, poly(acrylic acid), poly(methacrylic acid), polymethacrylates, copolymers loli(methylmethacrylate), polyacrylamid and alginic acid currently considered unsuitable to obtain formulations according to this invention.

Matrix based on polymethacrylates (for example, Eudragit®RS30D and Eudragit®RL30D) or contain relevant quantities of swelling in water of the material, especially hydroxyethylcellulose, such as a receiver array, currently considered unsuitable for applications in which anomo invention.

Currently alkylaryl, as a rule, are also considered unsuitable to obtain formulations according to this invention. Propylethylene, for example, shows a strong lipophilic properties to get from it the matrix with features release on this invention. The methylcellulose is also not suitable for the formulations according to this invention.

According to the invention a matrix that provides a prolonged release of the active compounds is chosen so that the release of the active compounds was prolongirovanne, invariant and, if there are multiple connections independently, and that the formulation was stable during storage. Preferably, such matrices contain polymers based on ethyl cellulose, and ethylcellulose is a particularly preferred polymer. Specifically preferred matrix containing polymers produced under the trademark Surelease®. Particularly preferred application of Surelease®E-7-7050.

Other methods of slowing down, braking, such as, for example, a film coating, which ensures a prolonged release, currently considered unsuitable to obtain formulations that provide the particular release of the active compounds according to izaberete is receiving. In addition, they are not considered as suitable to obtain formulations that ensure the stability of the formulations when stored.

For formulations according to this invention, which contain nanabhoy diffusion matrix based on ethyl cellulose, ethyl cellulose (or Surelease®E-7-7050) in the matrix varies, comprising 1-15%, preferably 3-12%, particularly preferably 5-9% and even more preferably 6-8%. The percentage indicates the amount of ethyl cellulose (or Surelease®) of the total weight of the preparation.

Formulation of preparations preferably contain fatty alcohol as the second component, in addition to cellulose, which causes the effect of prolonged action. The fatty alcohol can be a lauric, ministerului, stearyl, cetylstearyl, ceremony and/or cetyl alcohol. The amount of fatty alcohol in the matrix is 5-30%, preferably 10-25%, and especially preferably 15-20%. Especially preferred is the amount of fatty alcohol is about 20% (if the matrix is produced by spray granulation) or about 18% (if the matrix is produced by extrusion). All percentage values show the amount of fatty alcohol to the total weight of the preparation.

Formulations with special release for this invention contain, in particular, matrices, including ethylcellulose is and at least one fatty alcohol as components that have a significant effect on the release characteristics of the matrix. The amount of ethyl cellulose and at least one fatty alcohol may vary significantly, so that you can obtain drugs with different release profiles. Even despite the fact that the preparations according to the invention usually contain both of the above component, in some cases it may be preferable that the preparations contained only ethylcellulose or fatty(e) alcohol(s) as components that determine the nature of the release.

The formulations of this invention may optionally contain additional components, which have the effect of prolonged release. However, you should ensure that the release of active compounds from the formulation and the stability during storage of the formulation are in accordance with the present invention and is not a negative impact. Such additional components with the effect of prolonged release can be a polyalkylene glycols, and particularly preferably glycols.

According to the invention formulations that provide release of the active compounds according to the invention can contain, in addition to materiaaleilla, fillers and additives, such as additives for granulation, lubricants, dyes, substances that increase the fluidity, and plasticizers.

As fillers can be applied lactose, glucose or sucrose, starches and their hydrolysates, microcrystalline cellulose, cellactose, sugar alcohols such as sorbitol or mannitol, poorly soluble calcium salts, such as dihydroorotase calcium, hydroalcoholic calcium or tricalcium phosphate.

Povidone can be used as substances that promote granulation.

As substances that increase the fluidity, and as a lubricant, preferably, it is possible to apply highly disperse silicon dioxide (Aerosil®), talc, corn starch, magnesium oxide and magnesium stearate and/or calcium.

As lubricants, preferably, you can apply stearate and/or calcium stearate. Also preferably possible to use fatty acids such as stearic acid, or fats such as castor oil.

As additives that affect the deceleration (prolongation), it is also possible to use glycols and fatty alcohols such as cetyl and/or stearyl alcohol and/or cetostearyl alcohol.

In the matrix composition for sustained release, you can include other pharmaceutically acceptable excipients known in tech is, such as surfactants, preservatives, diluents, agents that promote granulation, dyes, fragrances, detergents, buffers, and/or agents, anti caking, if the formula still provides features release by this invention, i.e. extended, invariant and, if there are multiple connections, independent release. Such formulations should also ensure good stability of the active compounds in the matrix during storage.

If you are fillers and additives, such as dyes and the above-mentioned lubricant, agents that promote fluidity, and plasticizers, you should apply the precautionary measures, according to the invention was applied only such combinations, which together with patriciabrasel substance, and/or such patriciabrasel substances, which guarantee the release profiles of the active compounds according to this invention.

All of these additional components of the formulation is chosen so that the matrix for the release of acquired character almost no swelling in water or swellable in the buffer and not the erosion of the diffusion matrix.

In accordance with the invention, especially preferred is a formulation that contains ethylcellulose or Surelease®E-7-7050 as macizorras is his substance, stearyl alcohol as a fatty alcohol, magnesium stearate as lubricant, lactose as a filler and povidone as an additive for granulation.

Matrix according to this invention can be used to obtain preparations which release the active compound prolongirovanne, independent and invariant and which releases the same amount of active substances per unit of time. Specifically, this means that in the case of the combination oxycodone/naloxone containing 12 mg of oxycodone and 4 mg naloxone, for the first 4 hours, released 25% of oxycodone and 25% of naloxone. Accordingly, in the case of the combination of oxycodone/naloxone, containing 24 mg of oxycodone and 8 mg naloxone, for the first 4 hours is allocated 25% of oxycodone and 25% of the naloxone, and in both cases, the deviation from the mean (which in this case is equal to 25% of oxycodone or naloxone) is not more than 20%.

This behavior is the same release of both active compounds may be desirable from the point of view of medical applications.

A preferred variant of the invention relates to preparations which release 1-40%, preferably 5-35%, more preferably 10-30%, and even more preferably 15-25% of oxycodone and/or naloxone for 15 minutes. In other preferred embodiments of the invention for 15 minutes released 15-20%, 20-25%, about the olo 15%, about 20% or about 25% of oxycodone and/or naloxone.

Another preferred variant of the invention relates to preparations which release 25-65%, preferably 30-60%, more preferably 35-55%, and more preferably 40-50% of oxycodone and/or naloxone for one hour. Preferred variants of the invention also apply to preparations which release 40-45%, 45-50%, about 40%, about 45% or about 50% of oxycodone and/or naloxone for one hour.

Another preferred variant of the invention relates to preparations which release 40-85%, preferably 45-80%, more preferably 45-75% and, more preferably 45-55%, 50-60%, 55-65%, 65-75%, or 75 to 85% of oxycodone and/or naloxone for 2 hours. Preferred options include drugs that release about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80% or about 85% of oxycodone and/or naloxone 2 hours.

One preferred variant of the invention relates to preparations which release 60-100%, preferably 75-95%, more preferably 85-95% and, more preferably, 80 to 90% of oxycodone and/or naloxone for 4 hours. Preferred variants of the invention also apply to preparations which release 80-85%, 85-90%, about 80%, about 85% or about 90% of oxycodone and/or naloxone in 4 hours.

One preferred variant of the invention on which is worn to drugs, which release of about 65-100%, preferably 75-100%, more preferably 80-95%, more preferably 80-85%, 85-90% or 90-95% of oxycodone and/or naloxone for 7 hours. Preferred variants of the invention also apply to preparations which release about 80%, about 85%, about 90% or about 95% of oxycodone and/or naloxone for 7 hours.

Another preferred variant of the invention relates to preparations which release 85-100%, preferably 90-100%, more preferably 95-100%, even more preferably about 95% or 100% of oxycodone and/or naloxone for 12 hours.

The preparations according to the invention can be obtained in the form of all commonly used forms, which are in principle applicable for preparations delayed (extended) action and which ensure that the active compounds are released in accordance with the invention. Particularly suitable tablets, multilayer tablets and capsules. You can use additional forms, such as granules or powders, and are acceptable only those forms that provide sufficient retardation and features of the release of this invention.

The pharmaceutical preparations can also contain a film coating. However, you should ensure that the coating will not have a negative impact on the particular release of the active is soedinenii from the matrix and on the stability of active compounds in the matrix during storage. Such film coating can be painted or, if necessary, may contain an initial dose of active compounds. These initial dose of the active compounds are released immediately, so that their effective level in the blood plasma is reached very quickly. You should ensure that the coverage of the preparations according to this invention did not adversely affect the features of the release of active compounds.

Active compounds that are part of this invention and which are released from the matrix according to the invention prolongirovanne, invariant and, if there are multiple connections independently, and also stably stored in the matrix, not limited to a specific class of compounds.

So, pharmaceutically active compounds for this invention include antipyretics, analgesics and anti-inflammatory agents such as indomethacin, aspirin, diclofenac, ibuprofen, anti-ulcer agents, such as sulpiride, vasodilators in heart failure, such as nifedipine, peripheral vasodilators, such as ifenprodil tartrate, antibiotics such as ampicillin, chloramphenicol or erythromycin, synthetic antimicrobial agents such as nalidixic acid, antispasmodics, such as propantheline bromide, antitussive and anti-asthma agent is, such as theophylline or aminophylline, bronchodilators, such as diprophylline, diuretics such as furosemide, muscle relaxants, such as chlorphenesin carbamate, agents that improve the performance of cerebral metabolism, such as meklofenoxat hydrochloride, mild tranquilizers, such as the oksazolov, diazepam or clotiazepam, strong tranquilizers, such as sulpiride, beta-blockers such as pindolol, antiarrhythmic agents, such as procainamide hydrochloride, anticoagulants, such as ticlopidine hydrochloride, antiepileptic, such as phenytoin, antihistamines, such as chlorpheniramine maleate, an antiemetic, such as difenidol hydrochloride, anti-hypertensive agents, such as dimethylaminoethylmethacrylate hydrochloride, sympathomimetic agents, such as digidroergotamina mesilate, expectorants, such as Bromhexine hydrochloride, oral antidiabetic agents such as glibenclamide, cardiovascular drugs, such as ubidecarenone, iron preparations such as ferrous sulfate ferrous iron, non-steroidal anti-inflammatory medicines or vitamins. Especially preferred are analgesics, including a group of opiates and opioids, such as oxycodone, morphine, Dihydrocodeine, Oxymorphone, buprenorphine or tramadol. Also prepact the tion are antagonists analgesics, such as naltrexone or naloxone. Other opioid agonists and antagonists can be found, for example, in International application WO 99/32119.

Especially preferred are formulations according to this invention, which as pharmaceutically active substances containing opioid analgesics (opioid antagonist) and/or opioid antagonists.

According to the invention opioid analgesics or opioid agonists include all compounds that belong to the class N2A of opioid analgesics according to the PBX according to the who classification, and who show an analgesic effect when applied according to this invention. Preferably, the opioid agonist selected from the group including morphine, oxycodone, hydromorphone, propoksifen, Nicomorphine, Dihydrocodeine, diamorphine, papaveretum, codeine, Ethylmorphine, phenylpiperidine and its derivatives, methadone, dextropropoxyphene, buprenorphine, pentazocine, Tilidine, tramadol, hydrocodone. Additional examples used in this invention analgesics include meperidine, Oxymorphone, Alphaprodine, Anileridine, dextromoramide, metopon, Levorphanol, phenazocine, ethoheptazine, propiram, profadol, phenampromide, tiamutin, pholcodeine, codeine, Dihydrocodeine, fentanyl, 3-TRANS-dimethylamino-4-phenyl-4-TRANS-carbethoxy-Λ'-cyclohexene, 3-dimethylamino-0-(4-methoxyphenylacetyl)-Pro is ifenna the oxime, (-)β-2'-hydroxy-2,9-dimethyl-5-phenyl-6,7-benzomorphan, (-)2'-hydroxy-2-(3-methyl-2-butenyl)-9-methyl-5-phenyl-6,7-benzomorphan, penitrated, (-)α-5,9-diethyl-2'-hydroxy-2-methyl-6,7-benzomorphan, ethyl ester 1-(2-dimethylaminoethyl)-4,5,6,7-tetrahydro-3-methyl-4-oxo-6-phenylindole-2-carboxylic acid, 1-benzoylmethyl-2,3-dimethyl-3-(m-hydroxyphenyl)-piperidine, N-allyl-7α(1-R-hydroxy-1-methylbutyl)-6,14-endo-econometria-neurorepair, (-)2'-hydroxy-2-methyl-6,7-benzomorphan, narutimetto, Phenoperidine, α-d1-methadol, α-1-methadol, β-d1-acetylmethadol, α-1-allmeadow and β-1-acetylmethadol. This list should not be considered as limiting.

Especially preferred are effective analgesic opioid agonists, such as oxycodone, hydrocodone, hydromorphone, morphine, codeine, Dihydrocodeine, methadone, Oxymorphone, fentanyl and Sufentanil. Specifically, the opioid agonist is a oxycodone.

According to the invention, the antagonists are compounds that neutralize the action (prevent the action of opioid agonists (as defined above). Such compounds can also be found in the PBX according to the who classification. According to the invention preferred are compounds that, when used according to the invention, reduce side effects, the effect of addiction and addictive potential, call the by opioid agonists. Antagonists can, along with others, naltrexone, naloxone, nalmefene, nalorfin, nalbuphine, naloxonazine, methylnaltrexone, etilzellazol, norbinaltorphimine, naltrindole, 6-β-naloxol and 6-β-naltrexol.

In particular, the preferred antagonists include naltrexone, nalmefene and naloxone. Especially preferred antagonist is naloxone.

According to the invention particularly preferred formulations containing a combination of oxycodone as agonist and naloxone as an antagonist. Preferably, the agonist is present in excess compared with the antagonist. Excess agonist determined on the basis of standard doses of the antagonist present in the combined drug. Quantitatively excess opioid agonist is usually expressed as the weight ratio of agonist to antagonist.

In the case of oxycodone and naloxone preferred weight ratio of agonist to antagonist is a maximum of 25:1, particularly preferred weight ratio 15:1, 10:1, 5:1, 4:1, 3:1, 2:1 and 1:1.

Used the absolute number of agonist and antagonist depend on the choice of active connections. According to the invention must be monitored closely to the agonist and the antagonist released from the pharmaceutical preparation is prepared for prolonged action, only independently and invari ntno.

If the combined drug use oxycodone and naloxone, up to standard doses taken, preferably 10-150 mg, particularly preferably 10-80 mg of oxycodone (usually applied quantity) and, preferably 1-50 mg of naloxone.

In other preferred embodiments of the invention, the preparations may contain 5-50 mg of oxycodone, 10-40 mg of oxycodone, 10-30 mg of oxycodone, or about 20 mg of oxycodone. Preferred variants of the invention may also include preparations containing 1-40 mg of naloxone, 1-30 mg naloxone, 1-20 mg of naloxone, 1-20 mg of naloxone or 1-10 mg of naloxone on the standard dose.

According to the invention the ratio of oxycodone and naloxone should be chosen in such a way as to ensure the release profiles according to the invention both active substances and to agonist could Express their analgesic effect, whereas the number of agonist is chosen so that it is reduced or stopped the action of the agonist that causes addiction or the addiction and side effects, (almost) without affecting the analgesic action of the agonist. According to the invention addictive and addiction, as well as persistent constipation and easing breathing should be considered as side effects effective analgesic opioid agonists.

Although this may not be underlined specifically, the term "agonist" and and "antagonist" always encompasses pharmaceutically acceptable and equally applicable derivative, salt, etc. for Example, if mentioned oxycodone or naloxone, it means, in addition to the free base, hydrochloride, sulfate, bisulfate, tartrate, nitrate, citrate, bitartrate, phosphate, malate, maleate, hydrobromide, hydroiodide, fumarate, succinate, etc.

According to the invention agonists and antagonists are prepared in the form of the drug so that they would be released from the obtained pharmaceutical preparation of prolongation, independent and invariant. This does not mean that the antagonist is in excess compared with the agonist. On the contrary, this means that preferably the formulations of the combination of agonist/antagonist, which has a release profile according to the invention, the agonist is in excess compared to the antagonist.

The preparations according to the invention for the treatment of pain, you can apply oral, nasal, rectal and/or by inhalation. According to the invention for parenteral use is not provided. Particularly preferred formulation for oral administration.

The formulations of this invention can be obtained by immobilization of the active compound in a matrix, for example, by melting, freezing when spraying, spray drying, granulation, direct pelletizing and/or extrusion.

Pharmaceutical preparations or products the preliminary stages of their receipt by this izaberete is s can be obtained by granulation with an increased build-up, escalation) and reduction (brake-down, grinding) of the particle size. The preferred option of the invention is a spray granulation, followed by drying of the granules. Another preferred variant of the invention is to obtain granules by granulation with enlargement (build-up) in the drum or granulation disk. The pellets can then be pressurized, for example, into tablets, using the known additives and methods.

Specialist in the art is familiar with methods of granulation used in the pharmaceutical industry. In the Examples options (see below) describes specific variants of the invention. However, within the competence of a person skilled in the art to adapt the process parameters to achieve specific goals.

Pharmaceutical formulations according to this invention or their predecessors, it is better to get extrusion (instead of granulation), as this allows you to omit several manufacturing steps (such as drying of the granules during granulation by spraying, so that the formulations according to the invention can be obtained more effectively and more cheaply.

As the receipt of the formulations according to this invention by extrusion is a continuous process, it is possible to omit several production stages (compared to other methods, such as spray granulation), re is the query result of the process of manufacture formulations according to this invention becomes more effective.

To obtain formulations of this invention by extrusion can be Surelease®E-7-7050, which contains as a plasticizer dibutylsebacate and other components, and to use directly ethylcellulose, as a result, the manufacturing process becomes cheaper and more efficient.

Obtaining pharmaceutical drugs or their precursors (products of the preceding stages) in accordance with the invention by extrusion is particularly advantageous. In one preferred variant of the invention, pharmaceutical preparations or their predecessors get forward and backward extrusion of the melt in a twin-screw extruders. Another preferred variant of the invention to provide a method of extrusion in the extruder with a single screw or with a large number of screws. These extruders may also include a mixer (mixing).

Extrusion is a well studied production processes in pharmaceutical technology and is well known to a person skilled in the art. Specialist in the art understands that in the extrusion process various parameters such as feed rate, the speed of the screw, the temperature in the different heating zones of the extruder (if possible), water content, etc. can be changed to obtain n the FL with the specified characteristics. In the section of Examples given many examples of the preparations according to the invention, obtained by extrusion.

The above parameters depend on the specific type of extruder. To obtain formulations of this invention, the extrusion can be performed in one - and mnogoshagovykh extruders, which can be screws rotating in the same or in opposite directions (extruders forward and reverse rotation). The feed rate of the components depends on the specific type of extruder.

The above parameters depend on the specific type of extruder. In the extrusion process, the temperature of the heating zones, in which the melting of the components of the formulation according to the invention can be 40-120°preferably 50-100°S, more preferably 50-90°S, even more preferably 50-70°and, most preferably, 50 to 65°With, especially when using twin-screw extruders with reverse rotation of the screw (such as a Leistritz Micro 18 GGL). Specialist in the art understands that not every heating zone to heat. In particular, in the area after the dispenser, where the components are mixed, it may be necessary cooling, approximately, up to 25°C. the Speed of the auger can vary from 100 to 500 revolutions per minute (rpm), preferably from 100 to 250 rpm, more preferably, is 100 to 200 rpm, most preferably, about 150 rpm, especially when using twin-screw extruders with obratnim rotation (protivovirusnym) screw (such as a Leistritz Micro 18 GGL). If necessary, you can select the geometry and the diameter of the Spinneret. The diameter of the nozzle is usually used extruders, as a rule, is 1-10 mm, preferably 2-8 mm and, most preferably, 3-5 mm. Different extruders may vary depending on the composition and include, for example, mixers (mixing). The ratio of length and diameter of the screw extruder, which can be used to obtain preparations according to the invention, generally, is about 40:1.

Typical vertical section of the screw that you can use to obtain the formulations according to the invention by extrusion, shown in Figures 1A and 1B. Methods of extrusion to obtain a pharmaceutical sustained-release preparations are well known to the person skilled in the technical field.

In a preferred embodiment of the invention using twin screw extruder with protivovirusnym (reverse rotation) of the augers to obtain formulations according to this invention. This may be an extruder type Micro 18 GGL (Leistritz AG, Nürnberg, Germany). The extruder for this preferred variant of the invention does not contain elements for mixing (see also Figure 1A). The velocity of the feed components, used to get the recipe, according to this invention is 1-3 kg/h, preferably 1-2 kg/hour. Particularly preferred feed rate of 1.5 kg/h. The temperature of the heating zones is 40-120°From 50 to 100°preferably 50-90°S, more preferably 50-70°C. a Particularly preferred temperature 50-65°C. the Extruder has 10 heating zones. In the first heating zone components are typically cooled to about 25°C. the temperature in the other heating zones, preferably, is about 50-65°and may vary for each heating zone. The speed of the auger is 1-500 rpm, preferably 1-250 rpm, more preferably 120 to 200 rpm, and more preferably, 150 rpm, the Diameter of the mouthpiece is 1-10 mm, preferably 2-8 mm and 3-5 mm In a particularly preferred variant of the invention the diameter of the mouthpiece is about 3 mm.

Typically, the temperature of the heating zones should be chosen in such a way that it is not destroyed pharmaceutically active compounds. The feed rate and the speed of the auger is chosen so that the pharmaceutically active compound was released from the drugs prolongirovanne, independent and invariant and were stable when stored in a matrix. For example, if the feed rate increases, the speed of the auger should be matched with the public to increase, to ensure the same, prolonged (slow).

Specialist in the art knows that all of the above parameters depend on the specific conditions of production (type extruder, the screw geometry, the number of components and so on) and can be adapted to the products obtained by extrusion, provided prolonged, independent and invariant release, as well as the aforementioned stability during storage. Specialist in the art knows how to properly adjust the above parameters.

Specialist in the art can from the Examples (see below) to conclude that by changing the parameters of the extrusion process and changing the composition in regard to the compounds mainly responsible for the particular release of the drugs, you can obtain drugs with different release profiles. Thus, the present invention allows for the first time (at first) to obtain the product with the specified profile release oxycodone and naloxone or naloxone, varying, for example, the number of fatty alcohols or patriciabrasel polymer ethyl cellulose, as well as production parameters, such as temperature, speed of the screw (in the extrusion process) or the pressure at reception of tablets.

After the resulting preparation with the specified profile wisweb the Denia specialist in the art can modify the preparations according to the invention the number of active compounds into preparations, as shown above. Drugs, containing various amounts of the active compounds, but, as for the rest of the components having almost the same composition, must have extended features, invariant and independent release.

Thus, in the Examples described many examples showing that drugs with different release profiles can be obtained by changing the number, for example, ethyl cellulose. In other examples, it is shown that, if the resulting preparation with a defined set profile release, the change in the number of naloxone will not affect the features of the release of such drugs, if the difference in the amount of active substance to replace pharmaceutically inert excipients, such as lactose.

Getting drugs in this invention by extrusion, preferably for formulations containing as active compounds for opioid analgesics and opioid antagonists. Particularly preferably obtain formulations of this invention containing oxycodone and naloxone, with the preferred weight ratio of agonist to antagonist is a maximum of 25:1, preferably, 20:1, 15:1, 10:1, 5:1, 2:1i 1:1.

A preferred variant of the invention refers to a drug that contains a matrix according to the invention and naloxone as pharmaceutically active compounds. These drugs are convenient to use in some other cases.

The preparations according to the invention containing as active compounds for opioid antagonists, such as naloxone, can be used, for example, for full or partial treatment caused by opioid side effects. Such side effects can include dizziness, loss of breath, abuse of opioids, the development of tolerance and addiction, and partially persistent constipation.

The preparations according to the invention, which contain naloxone as pharmaceutically active compounds, preferably used for treatment caused by opioids for persistent constipation. Almost 90% of patients receiving treatment opioids, there are signs of persistent constipation, which may be responsible for other ailments, such as discomfort, heaviness and pain in the abdomen, nausea and vomiting, anorexia, hemorrhoids, anal fissures, encopresis have paradoxical diarrhea, urinary retention, "false" obstruction of the intestine, and the ulcers of the colon, which can lead to perforation (Neuenschander et al. (2002), Palliativmedizin au feinem Blick, Schweizerische Krebsliga).

The advantage of using preparato is according to the invention, contains naloxone, is that they provide a prolonged action of the antagonist naloxone. For example, if patients are experiencing pain, at the same time to give opioid analgesics, the use of such drugs, containing naloxone, makes vozmojnym prolonged treatment caused by opioid side effects, including persistent constipation. In particular, the use of naloxone in the form of recipes prolonged action can effectively treat caused by opioids for persistent constipation. At the same time while receiving this ensures that you will not develop tolerance to opioid analgesics. In addition, the use of naloxone does not lead to any violation of the metabolism of water and electrolytes and does not cause irritation of the colon.

The presence recipe prolonged action, containing as the sole active compounds naloxone has also the advantage that patients who are treated with opioid analgesics, can get a dose of naloxone sufficient for neutralization (reaction) caused by opioids side effects without a noticeable decrease in analgesia. With availability of the preparations according to the invention, which contain different amounts of naloxone, it becomes possible to specifically treat the needy in the treatment of pain patients who Paul is widely different amounts of opioid agonists or different opioid agonists.

Another preferred variant of the invention relates to the use of drugs according to the invention, containing naloxone for treatment caused by opioids itching. Itching caused by opioids, is one of feel sick side effects, extremely unpleasant.

In another embodiment of the invention, preparations containing naloxone, can also be used for the treatment of idiopathic syndromes, such as pruritus of unknown origin or itching caused by cholestasis and/or renal dysfunction. These drugs can also be used for the treatment of chronic idiopathic itch or irritable bowel syndrome. So, the preparations according to this invention, containing naloxone as pharmaceutically active compounds, can be applied in many medical reasons and for many purposes that can be associated or not associated with opioids. As the preparations according to the invention provide a prolonged and reproducibly invariant release, they can effectively treat the above syndromes.

In a preferred embodiment, the preparations according to this invention, containing naloxone as an active connection, free of 30-60%, preferably 35-55%, more preferably 40-50%, and even more preferably 40-45% or 45-50% of naloxone for 90 minutes. In another preferred is a variant of the invention, drugs, contains naloxone, release of about 40%, about 45% or about 50% of the active compound in 90 minutes.

In another prior embodiment, the preparations according to the invention, containing naloxone, release 30-70%, preferably 35-65%, and more preferably 40-60% of naloxone for 120 minutes. In another embodiment of the invention, preparations containing naloxone, release, preferably, 35-40%, 40-45% 45-50% of naloxone for 120 minutes. In another preferred variant of the invention, the preparations containing naloxone, release about 35%, about 40%, about 45%, about 50% or about 55% of naloxone for 120 minutes.

In another preferred embodiment, the preparations according to this invention, contains naloxone, release 55-90%, preferably 60-80%, more preferably 65-75%, even more preferably 65-70% or 70-75% of naloxone for 420 minutes. In another preferred variant of the invention, the preparations containing naloxone, release about 65%, about 70% or about 75% of naloxone for 420 minutes.

In another preferred embodiment, the preparations according to the invention, containing naloxone, release 60-90%, preferably 65-85%, more preferably 70-80%, even more preferably 75-80% of naloxone for 600 minutes. In another preferred variant of the invention, the preparations containing naloxone, release about 75%, about 80% or about 85% of naloxone for 600 minutes.

Note the measures that show has great advantages variants of the invention presented below. It also provides examples that show that the formulations according to the invention are distinguished mainly by its structure from formulations with prolonged action, which receive conventional carisoorodol polymers. Only formulations obtained according to the invention provide a prolonged, invariant and, if you have multiple connections, independent release of the active compounds and are formulations, stable during storage. The examples should not be construed as limiting the possible variants of the invention.

Example 1 - Getting tablets with varying amounts of oxycodone/naloxone in kinabuhayan diffusion matrix method of granulation by spraying.

To obtain tablets of oxycodone/naloxone according to the invention using the following quantities enumerated components:

Drug (designation)Oxy/Nal-0Oxy/Nal-5Oxy/Nal-10
Oxycodone HCl20.0 mg20.0 mg20.0 mg
Naloxone HCl-5.0 mg10.0 mg
Lactose Lac Flow 10059.25 mg54.25 mg49.25 m the
Povidone 305.0 mg5.0 mg5.0 mg
Surelease®10.0 mg of dry material10.0 dry material10.0 dry material
Stearyl alcohol25.0 mg25.0 mg25.0 mg
Talc2.5 mg2.5 mg2.5 mg
Mg-stearate1.25 mg1.25 mg1.25 mg

Apply the mixture of polymer Surelease E-7-7050 has the following composition:

Surelease®
Ethylcellulose 20 cpi
Dibutylsebacate
The ammonium hydroxide
Oleic acid
Silicon dioxide
Water

To obtain tablets oxycodone HCl, naloxone HCl, povidone 30 and lactose Lac Flow 100 is mixed in a rotating drum mixer (Bohle) and then granularit spray with Surelease®E-7-7050 on equipment for granulation in the fluidized bed (GPCG3). The material is sifted through a sieve Comill 1.4 see Additional step of granulation is carried out with molten fatty alcohol in smesitel the high shear (demand include Collette). All cores thus obtained tablets weigh, in terms of dry substance, 123 mg.

Example 2 - getting a tablet of oxycodone and naloxone in the not-swellable diffusion matrix by extrusion.

To obtain tablets of oxycodone/naloxone according to the invention using the following quantities enumerated components:

Drug (designation)Oxy/Nal-Extr
Oxycodone HCl20 mg
Naloxone HCl10 mg
Kollidon 30b mg
Lactose Lac Flow 10049.25 mg
Ethylcellulose 45 cpi10 mg
Stearyl alcohol24.0 mg
Talc2.5 mg
Mg-stearate1.25 mg

Listed number of oxycodone HCl and naloxone HCl, ethyl cellulose 45 cpi, kollidon, stearyl alcohol and lactose Lac Flow 100 is mixed in a rotating drum mixer (Bohle). Then this mixture ekstragiruyut in co-rotating twin screw extruder with protivovirusnym type Micro 18 GGL (Leistritz AG, Nürnberg, Germany). The temperature of the heating zone 1 is 25°C, the temperature of the heating zone 2 is 50°temperatures of the heating zones 3-5 60°C, the temperature of the unit's electric the different zones 6-8 55° With the temperature of the heating zone 9 is 60°and the temperature of the heating zone 10 is 65°C. the Speed of rotation of the augers is 150 revolutions per minute (rpm), the final temperature of the melt is 87°S, feed rate of 1.5 kg/h and the hole diameter of the nozzle 3 mm Extruded material is sifted through a sieve Frewitt 0.68×100 mm Then crushed extrudate is mixed with talc and magnesium stearate, which is added through the hand sieve of 1 mm, and then pressed into tablets. The extruder has a screw geometry, shown in Figa.

Compared to tablets of oxycodone/naloxone, which also have not swellable diffusion matrix on the basis of Surelease®obtained by granulation by spraying method (see Example 1), extruded products contain fewer components.

Example 3 - Profile release tablets of oxycodone/naloxone Example 1.

The release of the active compounds measured within 12 hours Basket method in accordance with USP at pH 12 using HPLC. Have tablets Oxy/Nal-0, Oxy/Nal-5 and Oxy/Nal-10.

From Figure 2 and the values listed in the Table, it is seen that in case of no swellable diffusion matrix on the basis of Surelease®speed of release of different amounts of oxycodone, regardless of the number of naloxone, remain the same (invariant). For the NGOs, invariant release profiles are observed for naloxone with different amounts of oxycodone.

Time (min)Ox/Nal-OOx/Nal-5-OOx/Nal-5-NOx/Nal-10-OOx/Nal-10-N
OkhaOkhaNalOkhaNal
000000
1526.124.923.522.824.1
12062.1636157.560.2
42091.794.591.989.493.5
72098.199.696.695.7100.6

The magnitude of the release related to oxycodone or naloxone (line 2) and is expressed in percent. The average value for the release of naloxone, for example, for 420 min is 92.7%. The maximum deviation at 420 min is 1%. Okha and Nal mean oxycodone and naloxone and show what an active connection is the dimension.

Example 4 - the release Profile of the tablets of oxycodone/naloxone from Example 2 at different pH values.

The release of the active is x connections from tablets define for 12 hours at pH 1.2 or within 1 hours at pH 1.2, and then for 11 hours at pH 6.5. Speed of release determines basket method in accordance with USP using HPLC.

The values below the speed of release is determined in 12 hours at pH 1.2:

Time (min)Oxy/Nal-Extr-1,2-OOxy/Nal-Extr-1,2-N
OkhaNal
000
1524.124.0
12062.963.5
42092.993.9
72096.998.1

The values below the speed of release is determined in the course of 1 hour at pH 1.2 and 11 hours at pH 6.5:

Time (min)Oxy/Nal-Extr-6,5-OOxy/Nal-Extr-6,5-N
OkhaNal
000
60.48.149.2
12065.064.7
24083.381.8
42094.192.3

The magnitude of the release related to oxycodone or naloxone (line 2) and is expressed in percent. Okha and Nal mean oxycodone and naloxone and who have, what active compound is the dimension.

Comparison of the values shown in the Table of Example 4 and in the Table of Example 3 clearly shows that regardless of the process of obtaining active compounds are released from products in equal amounts. For example, 89.4% of the oxycodone is released for 420 minutes of tablets obtained by spray granulation (pill Ox/Nal-10, see Example 3), whereas extruded tablets (Ox/Nal-Extr-1,2-O, Example 4) for 420 minutes released 92.9%. Thus, the deflection of the release of oxycodone from extruded tablets from the mean values of the release of oxycodone from the tablet obtained by the method of granulation by spraying (91.9% for 420 minutes), is 1.1%. 93.5% of Naloxone is released for 420 minutes of tablets obtained by spray granulation (pill Ox/Nal-10, see Example 3), whereas extruded tablets (Ox/Nal-Extr-1,2-O, Example 4) for 420 minutes released 93.9%. The deflection release naloxone extruded tablets from the mean values of the release of oxycodone from the tablet obtained by the method of granulation by spraying (92.7% for 420 minutes), is 1.3%.

In addition, when comparing the values in the Tables of Example 4 and in Figures 3A and 3B that, regardless of the pH value at which the velocity is determined wisweb the Denia release oxycodone and naloxone remains the same and invariant.

Example 5 is a Comparative example: release tablets Valoron®.

Monitoring of the release of active substance from the tablets should be performed within 7 hours. Tablets Valoron®containing 50 mg of Tilidine and 4 mg naloxone (Ti/Nal-50/4), or 100 mg Tilidine and 8 mg naloxone (Ti/Nal-100/8), or 150 mg Tilidine and 12 mg of naloxone (Ti/Nal-150/12), experiencing the Basket method in accordance with USP for 1 hour at pH 1.2, then for 6 h at pH 6.5 using HPLC.

In Figures 4A and 4B and from the values shown in the Table, it is seen that in the case of swelling (and possibly erosion) diffusion matrix with the relevant quantities receiver array release different amounts of Tilidine varies considerably and is not invariant for different amounts of naloxone. In turn, this applies to the naloxone. This means that for a given pH, the release of the active compounds is not independent from each other.

Time (min)Ti/Nal-50/4-TTi/Nal-50/4-NTi/Nal-100/8-TTi/Nal-100/8-NTi/Nal-150/12-TTi/Nal-150/12-N
TilNalTilNalTilNal
0 000000
6037.227.633.927.329.923.3
12047.631.746.533.441.528.5
18054.737.45541.248.235
24059.74468.259.554.540.1
30065.250.682.672.960.547.5
36070.35885.782.767.256.4
42074.260.893.190.984.978.9

The magnitude of the release are Tilidine or naloxone (line 2) and is expressed in percent. The average release of naloxone, for example, for 420 min is 78.87%. The maximum deviation for 420 minutes is 20.4%. Til and denote the Nal Tilidine and naloxone and show what an active connection is the dimension.

Example 6 Comparison of the structure of the tablets of Examples 1 and 2 tablets Valoron®by electron microscopy the AI.

For study by electron microscopy choose a tablet, containing 20 mg of oxycodone and 10 mg of naloxone and obtained either by spray granulation in accordance with Example 1 (Ox/Nal-10), or by extrusion in accordance with Example 2 (Oxy/Nal-Extr). In addition, the use of tablets Valoron®containing 100 mg of Tilidine and 8 mg naloxone. In Figures 5A and 5B shows obtained by scanning electron microscopy at different magnification images of the tablets Ox/Nal-10 composition of this invention obtained by the method of granulation by spraying. In Figures 6A and 6B shows obtained by scanning electron microscopy pictures of pills Oxy/Nal-Extr composition according to this invention, obtained by extrusion. In Figures 7A and 7B shows obtained by scanning electron microscopy pictures of the pill Valoron®N.

When comparing the figures, we can clearly see that the tablet formulation according to the invention have a surface substantially thinner and more homogeneous microstructure, with fewer cracks than tablets Valoron®that regardless of if the tablet granulation by spraying or extrusion. The structural differences are a possible cause of the different features of the release of different drugs.

Example 7 to Obtain tablets containing time the ranks of the number of naloxone and different matrices, granulation by spraying.

To obtain naloxone use the following quantities of listed components:

Drug (designation)Nal-5-EURNal-5-SureNal-10-Sure
Naloxone HCl5.0 mg5.0 mg10.0
Lactose Lac Flow 10074.2574.2569.25
Povidone 305.05.05.0
EUDRAGIT®RS 30D10 mg of dry material--
Surelease®-10 mg of dry material10 mg of dry material
Triacetin2.0 mg--
Stearyl alcohol25.0 mg25.0 mg25.0 mg
Talc2.5 mg2.5 mg2.5 mg
Mg-stearate1.25 mg1.25 mg1.25 mg

EUDRAGIT®RS 30D can be obtained from Röhm GmbH, Darmstadt. Surelease®can be obtained from the use Ltd, Idstein.

Use of a polymeric mixture of EUDRAGIT®RS 30D and Surelease®of the following composition:

EUDRAGIT�AE; RS 30DSurelease
The copolymer, ammonium methacrylateEthylcellulose 20 cpi
Sorbic acidDibutylsebacate
Sodium hydroxideThe ammonium hydroxide
WaterOleic acid
Silicon dioxide
Water

To obtain tablets naloxone HCl, povidone 30 and lactose Lac Flow 100 is mixed in a rotating drum mixer (Bohle) and then granularit spray with EUDRAGIT® RS 30D or Surelease®on installation for granulation in the fluidized bed (GPCG3). The additional step of granulation is carried out with molten fatty alcohol in the mixer with a high shear (demand include Collette). All cores thus obtained tablets weigh, in terms of dry substance, 125 mg.

Example 8 to Obtain tablets with naloxone and not swellable diffusion matrix by extrusion.

To obtain naloxone tablets according to the invention using the following quantities enumerated components:

Drug (designation)Nal-Extr
naloxone HCl10 mg
Lactose Lac Flow 10070.25 mg
Kollidon 305 mg
Ethylcellulose 45 cpi8 mg
Stearyl alcohol26.0 mg
Talc2.5 mg
Mg-stearate1.25 mg

Listed number of naloxone HCl, ethyl cellulose 45 cpi, kollidon, stearyl alcohol and lactose Lac Flow 100 is mixed in a rotating drum mixer (Bohle). Then this mixture ekstragiruyut in co-rotating twin screw extruder with protivovirusnym type Micro 18 GGL (Leistritz AG, Nürnberg, Germany). The temperature of the heating zone 1 is 25°C, the temperature of the heating zone 2 is 50°temperatures of the heating zones 3-10 55°C. the Speed of rotation of the augers is 140 revolutions per minute (rpm), the temperature of the resulting melt is 65°S, feed rate of 1.25 kg/h and the hole diameter of the nozzle 3 mm Extruded material is sifted through a sieve Frewitt 0.68×100 mm Then crushed extrudate is mixed with talc and magnesium stearate, which is added through the hand sieve 1 mm, and then pressed into tablets. The extruder has a screw geometry, shown in figure 1.

Compared to tablets of oxycodone/naloxone, which also have not swellable diffusion matrix on the basis of Surelease®obtained by granulation by spraying method (see Example 7), extruded products contain less components the clients.

Example 9 - release tablets naloxone from Example 7

The release of the active connections that determine for 16 hours by the Basket method in accordance with USP at pH 1.2 using HPLC. Conduct testing of two tablets (labeled a and b) Nal-5-EUR, Nal-5-Sure and Nal-1-Sure.

In Figures 8A and 8B and of the values shown in the Table, it is seen that in case of no swellable diffusion matrix on the basis of Surelease®speed of release of naloxone regardless of the absolute number reproducibly do not change and remain almost equal to the (invariant). This does not apply to the release of naloxone from a matrix based on Eudragit®.

Time (min)Nal-5-EUR-ANal-5-EUR-BNal-5-Sure-ANal-5-Sure-BNal-10-Sure-ANal-10-Sure-B
0000000
1518.4818.2323.8621.9720.6522.25
9040.4626.1546.7447.3345.1845.98
24062.4353.4770.4869.4969.1368.76
420 82.972.2791.0488.6988.0687.05
72097.4685.74100.6299.196.0596.75
960107.696.25102.26102.3397.9197.43

The magnitude of the release are naloxone and expressed in percent. The average value for the release of naloxone, for example, tablets Nal-Sure for 90 min is 46.3%. The maximum deviation at 90 min is 2.2%. The average value at this point in time for tablets Nal-EUR is 33.3%, and the deviation is 21.5%.

Example 10 - release tablets naloxone from Example 8.

The release of active compound is determined for different tablets within 12 hours of the Basket method in accordance with USP at pH 1.2 using HPLC.

In the Figure 9 and from the values shown in the Table, it is seen that the release of naloxone regardless of the method of obtaining reproducible does not change when the tablet is produced by extrusion.

Time (min)Nal-Extr-ANal-Extr-BNal-Extr-C
0000
1515154.3
12040.741.940.1
4207275.273.6
72090.192.491.2

The magnitude of the release are naloxone and expressed in percent. The average value for the release of naloxone in the case of tablets Nal-Extr for 120 min is of 40.9%. The maximum deviation in the time point 120 min is 2.4%.

Example 11 comparison of the patterns of naloxone tablets of Examples 7 and 8.

For study by electron microscopy using tablets Nal-Extr from Example 7, containing 5 mg (Nal-5-Extr), as well as pills Nal-Extr from Example 8.

In Figures 10A and 10B shows pictures of the pill Nal-5-EUR, made by scanning electron microscopy at different magnifications. In Figures 11A and 11B shows pictures of the pill Nal-Extr composition according to this invention, made by scanning electron microscopy at different magnifications.

When comparing the figures, we can clearly see that the tablet formulation according to the invention have a surface substantially thinner and more homogeneous structure. In particular, Figures 10A and 10B, but not in Figures 11A and 11B can see the plaque (blushing) naloxone. The structural differences are a possible cause of the different features of visvobodi the Oia of conduct for the release of different drugs.

Example 12 Comparison of the structure of the granules of naloxone from Examples 7 and 8.

For study by electron microscopy using the pellets used to produce tablets of Example 7, containing 10 mg (Nal-10-Sure), and tablets Nal-Extr from Example 8.

In Figures 12A and 12B shows images of tablets and granules Nal-10-Sure made by scanning electron microscopy at different magnifications. In Figures 13A and 13B shows snapshots of granules Nal-Extr composition according to this invention, made by scanning electron microscopy at different magnifications.

When comparing the figures, we can clearly see that regardless of the method of producing pellets with a formulation according to the invention have a homogeneous structured surface, without big cracks or raids. Not wishing to be bound by scientific theory, applicants believe that the features of the structure are responsible for the features of the release (behavior release) preparations according to this invention.

Example 13 Stability during storage of naloxone tablets depending on the matrix.

Different tablets containing Eudragit®RS30D or Surelease®and 5 mg of naloxone receive as described in Example 1. Tablets stored at a temperature of 25°and at a relative humidity of 60%. The release definition is between different time points, as described in Example 4.

As can be seen in Figures 4A and 4B and Table, the release profiles of the tablets of naloxone, prepared with Eudragit®RS30D, are already after short-term storage. On the contrary, the release profiles of the tablets prepared with Surelease®are almost invariant even after 15 months of storage.

Storage time (months)013.5
Drug (designation)Nal-5-EUR-0Nal-5-EUR-1Nal-5-EUR-3.5
Time (min)
1516.4612.6615.06
9030.2928.7830.6
240At 52.9443.8547.5
48071.0757.3762.86
72083.2966.6873.58
102091.6173.0880.97

Storage time (months)03615
Drug (designation)Nal-5-Sure-0Nal-5-Sure-3Nal-5-Sure-6
Time (min)
1521.5822.5216.0424.36
12049.9449.0551.9355.59
42079.8386.3287.9988.49
72091.7497.55100.2797.09

In the Table, the speed of release is given in percent. In each case, determine the release of naloxone.

Example 14 to Obtain tablets with varying amounts of oxycodone/naloxone in the not-swellable diffusion matrix by extrusion:

For the preparation of tablets of oxycodone/naloxone according to the invention using the following quantities of listed components:

Drug (designation)OxN20/1-Extr-AOxN20/1-Extr-BOxN20/1-Extr-COxN20/10-Extr-A
Oxycodone HCl20 mg20 mg20 mg20 mg
Naloxone HCl1 mg1 mg1 mg10 mg
Lactose Lac Flow 10058.25 mg58.25 mg58.25 mg49.25 mg
Kollidon®306 mg6 mg6 m the b mg
Ethylcellulose10 mg10 mg10 mg10 mg
Stearyl alcohol24 mg24 mg24 mg24 mg
Talc1.25 mg1.25 mg1.25 mg1.25 mg
Mg-stearate2.5 mg2.5 mg2.5 mg2.5 mg

The extrusion is carried out, as described above (Example 2), the parameters below:

OxN20/l-Extr-A:temperature:55 to 63°
rpm (screw):150 rpm
feed speed:1.5 kg/h
OxN20/1-Extr-B:temperature:55 to 63°
rpm (screw):155 rpm
feed speed:1.5 kg/h
OxN20/1-Extr-C:temperature:55 to 63°
rpm (screw):150.5 rpm (?)
feed speed:1.5 kg/h
OxN20/10-Extr-A:temperature:55 to 63°
ÈA; rpm (screw):160 rpm
feed speed:1.75 kg/hour

Tablets get on a normal device for tableting with the following settings:

OxN20/1-Extr - A:rpm:40 rpm
pressure:9 kN
OxN20/1-Extr-In:rpm:42 rpm
pressure:8.9 kN
OxN20/1-Extr-From:rpm:36 rpm
pressure:9 kN
OxN20/10-Extr-A:rpm:36 rpm
pressure:7.9 kN

The release of the active compounds determined within 12 hours of the Basket method in accordance with USP at pH 1.2 using HPLC. Check tablets OxN20/1-Extr-A, OxN20/1-Extr - In, OxN20/1-Extr-and OxN20/1.0-Extr-A

From the values shown in the Table, it is seen that in case of no swellable diffusion matrix based on ethyl cellulose speed of release of different amounts of naloxone, regardless of the number of oxycodone, remain practically the same. Therefore, drugs provide independent and invariant in the release of active compounds.

Time (min)OxN20/1-Extr-AOxN20/1-Extr-BOxN20/1-Extr-COxN20/10-Extr-A
OxyNalOxyNalOxyNalOxyNal
000000000
1521.225.821.721.119.719.323.324.3
12056.653.858.857.357.756.264.566.9
42087.284.594.292.693.791.592.796.3
72099.796.8100.198100.697.593.797.4

The magnitude of the release related to oxycodone or naloxone (line 2) and is expressed in percent. The average value for the release of naloxone, for example, for 420 min is 92.3%. The maximum deviation at 420 min is 7.4%. Oxy and Nal mean oxycodone and n is loxon and show what active compound is the dimension.

Thus, when a drug with a specific release profile obtained, you can change the number of active substances without any noticeable change in the profile of release of active compounds. Drugs, containing various amounts of active connections still provide a prolonged, independent and invariant release of the active compounds.

Example 15 to Obtain tablets containing oxycodone/naloxone in kinabuhayan diffusion matrix by extrusion.

The following example shows that, using the formulations of this invention, it is possible to obtain preparations containing oxycodone and naloxone with the specific features of the release.

For the preparation of tablets of oxycodone/naloxone according to the invention using the following quantities of listed components:

Drug (designation)OxN20/ 1-Extr-DOxN20/1-Extr-EOxN20/10-Extr-BOxN20/10-Extr-COxN20/10-Extr-DOxN20/10-Extr-E
Oxycodone HCl20 mg20 mg20 mg20 mg20 mg20 mg
Naloxone HCl1 mg1 mg10 mg10 mg 10 mg10 mg
The Flow lactose Lac56.25 mg56.25 mg54.25 mg65.25 mg60.25 mg55.25 mg
Kollidon®307 mg6 mgb mg7.25 mg7.25 mg7.25 mg
Ethylcellulose11 mg12 mg10 mg12 mg12 mg12 mg
Stearyl alcohol24 mg24 mg24 mg28.75 mg28.75 mg28.75 mg
Talc1.25 mg1.25 mg1.25 mg1.25 mg1.25 mg1.25 mg
Mg-stearate2.5 mg2.5 mg2.5 mg2.5 mg2.5 mg2.5 mg

The extrusion is carried out, as described above (Example 2), the parameters below:

OxN20/1 - Extr-D: temperature:55 to 63°
rpm (screw):150 rpm
feed speed:1.5 kg/h
OxN20/1 - Extr-E: temperature:55 to 63°
rpm (screw):150 rpm
the speed on the ACI: 1.5 kg/h
OxN20/10-Extr-In: temperature:55 to 63°
rpm (screw):160 rpm
feed speed:1.75 kg/hour
OxN20/10 - Extr: temperature:55 to 63°
rpm (screw):160 rpm
feed speed:1.75 kg/hour
OxN20/10 - Extr-D: temperature:55 to 63°
rpm (screw):150 rpm
feed speed:1.5 kg/h
OxN20/10 - Extr-E: temperature:55 to 63°
rpm (screw):150 rpm
feed speed:1.5 kg/h

Tablets get on a normal device for tableting with the following settings:

OxN20/1-Extr-D:rpm:39 rpm
pressure:11 kN
OxN20/1-Extr-E:rpm:39 rpm
pressure:10.5 kN
OxN20/10-Extr-In:rpm:36 rpm
pressure:9.5 kN
OxN20/10-Extr-C:rpm: 36 rpm
pressure:7.8 kN
OxN20/10-Extr-D:rpm:39 rpm
pressure:9 kN
OxN20/10-Extr-E:rpm:39 rpm
pressure:7.5 kN

The release of the active compounds determined within 12 hours of the Basket method in accordance with USP at pH 1.2 using HPLC. Check tablets OxN20/1-Extr-D, OxN20/1-Extr-E, OxN20/10-Extr-B, OxN20/10-Extr-C, OxN20/10-Extr-D and OxN20/10-Extr-E.

Time (min)OxN20/1-

Extr-D
OxN20/1-

Extr-E
OxN20/10-

Extr-B
OxN20/10-

Extr-C
OxN20/10-

Extr-D
OxN20/10-

Extr-E
OkhaNalOkhaNalOkhaNalOkhaNalOkhaNalOkhaNal
0000000000000
1516.616.2 17.417.226.126.821.821.918.518.218.418.2
12047.646.949.649.771.173.061.261.852.852.853.353.3
42082.784.584.685.794.394.694.294.786.386.387.288.2
720959795.295.894.997.796.497.994.894.895.796.5

The magnitude of the release related to oxycodone or naloxone (line 2) and is expressed in percent. Okha and Nal mean oxycodone and naloxone and show what an active connection is the dimension.

This example shows that drugs with a specific release profiles can be obtained if the components of the matrix, which have a significant effect on the release characteristics of drugs, to apply ethylcellulose and fatty alcohols. When a drug with a specific release profile obtained, you can change to the number of active substances. Drugs, containing various amounts of active connections still provide a prolonged, independent and invariant release of the active compounds (see Example 14).

Example 16 to Obtain tablets containing naloxone in kinabuhayan diffusion matrix by extrusion.

For the preparation of naloxone tablets according to the invention using the following quantities of listed components:

Drug (designation)N10-Extr-1N10-Extr-2N10-Extr-3N10-Extr-4N10-Extr-5N10/-Extr-6
Naloxone HCl10 mg10 mg10 mg10 mg10 mg10 mg
The Flow lactose Lac69.25 mg69.25 mg69.25 mg69.25 mg69.25 mg69.25 mg
Povidone 305.0 mg5.0 mg5.0 mg5.0 mg5.0 mg5.0 mg
Ethylcellulose10 mg10 mg10 mg10 mg10 mg10 mg
Stearyl alcohol25 mg25 mg25 mg25 mg25 mg25 mg
Talc1.25 mg1.25 mg1.25 mg1.25 mg1.25 mg1.25 mg
Mg-stearate2.5 mg2.5 mg2.5 mg2.5 mg2.5 mg2.5 mg

The extrusion is carried out, as described previously, the parameters below:

N10-Extr-1:temperature:55 to 63°
rpm (screw):120 rpm
feed speed:1.5 kg/h
N10-Extr-2:temperature:55 to 63°
rpm (screw):140 rpm
feed speed:1.5 kg/h
N10-Extr-3:temperature:55 to 63°
rpm (screw):160 rpm
feed speed:1.75 kg/hour
N10-Extr-4:temperature:55°
rpm (screw):120 rpm
feed speed:1.75 kg/hour
N10-Extr-5:temperature:5° With(?)
rpm (screw):140 rpm
feed speed:1.5 kg/h
NIO-Extr-6:temperature:55°
rpm (screw):160 rpm
feed speed:1.5 kg/h

Tablets get on a normal device for tableting with the following settings:

N10-Extr-1:rpm:39 rpm
pressure:11.6 kN
N10-Extr-2:rpm:39 rpm
pressure:12.5 kN
N10-Extr-3:rpm:39 rpm
pressure:11.6 kN
N10-Extr-4:rpm:36 rpm
pressure:14.5 kN
N10-Extr-5:rpm:36 rpm
pressure:15.0 kN
N10-Extr-6:rpm:36 rpm
pressure:15.0 kN

Viswa is of an unforgettable active compounds determined within 12 hours of the Basket method in accordance with USP at pH 1.2 using HPLC. Check tablet N10-Extr-A, N10-Extr-B, N10-Extr-C, N10-Extr-D, N10-Extr-E and N10-Extr-F.

On the basis of the values shown in the Table, it is clear that in case of no swellable diffusion matrix based on ethyl cellulose and fatty alcohol speed of release of naloxone remain almost the same (invariant).

Time (min)N10-Extr-1N10-Extr-2N10-Extr-3N10-Extr-4N10-Extr-5N10-Extr-6
0000000
1513.012.913.013.213.313.5
12037.437.637.937.637.938.7
4206767.367.967.567.469.5
60078.178.578.778.478.380.5

The magnitude of the release are naloxone and expressed in percent. The average value for the release of naloxone, for example, for 420 min is 67.8%. The maximum deviation at 420 min is 2.5%.

1. The pharmaceutical composition providing a prolonged,invariant and independent release of pharmaceutically active substances, containing at least two pharmaceutically active compounds in the matrix, wherein the matrix is made of ethyl cellulose or polymer, based on ethyl cellulose and at least one fatty alcohol, and the matrix is diffusion and almost no swelling, and as pharmaceutically active compounds of the composition comprises at least one opioid analgesic selected from the group including morphine, oxycodone, hydromorphone, propoksifen, Nicomorphine, Dihydrocodeine, diamorphine, papaveretum, codeine, Ethylmorphine, phenylpiperidine and its derivatives, methadone, dextropropoxyphene, buprenorphine, pentazocine, tilidin, tramadol and hydrocodone, and at least one opioid antagonist selected from the group comprising naltrexone, naloxone, nalmefene, nalorfin, nalbuphine, naloxonazine, methylnaltrexone, etilzellazol, norbinaltorphimine, naltrindole, 6-β-naloxol and 6-β- naltrexol.

2. The pharmaceutical composition according to claim 1, characterized in that the fatty alcohol is a lauric, ministerului, stearyl, cetylstearyl, ceremony and/or cetyl alcohol, preferably stearyl alcohol.

3. The pharmaceutical composition according to claim 1, characterized in that the matrix is made of ethyl cellulose.

4. The pharmaceutical composition according to claim 1, characterized in that it contains is separated by conventional pharmaceutical excipients, mainly fillers, lubricants, additives that increase the fluidity, and/or plasticizers.

5. The pharmaceutical composition according to claim 4, wherein the fillers are selected from the group consisting of sugar, preferably lactose, glucose and/or sucrose, starches and their hydrolysates, preferably microcrystalline cellulose and/or cellactose, alcohols - derivatives of sugars, preferably sorbitol and/or mannitol, low-soluble calcium salts, preferably hydroalcoholic calcium, dihydroorotase calcium or phosphate of calcium and/or povidone.

6. The pharmaceutical composition according to claim 4, characterized in that as a lubricant it contains magnesium stearate, calcium stearate and/or calcium laurate, and/or fatty acid, preferably stearic acid.

7. The pharmaceutical composition according to claim 4, wherein the agent that increases the fluidity, it contains highly dispersed silicon dioxide, preferably Aerosil, talc, maize starch, magnesium oxide, magnesium stearate and/or calcium.

8. The pharmaceutical composition according to claim 4, characterized in that as a plasticizer, it contains dibutylsebacate.

9. The pharmaceutical composition according to claim 1, wherein the opioid analgesic and antagonist are present in the form of their pharmaceutically acceptable and have the same active is thew derivatives, such as a free base, salt, preferably the hydrochloride, sulfate, bisulfate, tartrate, nitrate, citrate, bitartrate, phosphate, malate, maleate, hydrobromide, hydroiodide, fumarata or succinate.

10. The pharmaceutical composition according to claim 1, characterized in that it contains oxycodone and naloxone, while oxycodone is present in an amount of 10-150 mg, preferably 10-80 mg and naloxone is present in the amount of 1-50 mg standard dose.

11. The pharmaceutical composition of claim 10, characterized in that it contains oxide and naloxone in a weight ratio of from 25:1 to 1:1, preferably from 20:1, 15:1 and more preferably 5:1, 4:1, 3:1, 2:1 and 1:1.

12. The pharmaceutical composition according to claim 1, characterized in that it is a tablet, preferably a multi-layer tablet, capsule, pills, granules or powder.

13. The pharmaceutical composition according to item 12, characterized in that it is suitable for oral, nasal and/or rectal application.

14. The pharmaceutical composition according to item 12, characterized in that it is obtained by granulation enlargement and/or reduction, preferably by spray granulation.

15. The pharmaceutical composition according to item 12, characterized in that it is produced by an extrusion method.

16. The pharmaceutical composition providing a prolonged invariant and independently researched is my release of pharmaceutically active substances, containing two pharmaceutically active compounds in the matrix, wherein the matrix is made of ethyl cellulose or polymer, based on ethyl cellulose and at least one fatty alcohol and is diffusion, almost no swelling and no erosion, and as the active compounds, the composition comprises oxycodone and naloxone, while oxycodone is present in an amount of 10-150 mg, preferably 10-80 mg and naloxone is present in the amount of 1-50 mg standard dose.

17. The pharmaceutical composition according to item 16, characterized in that oxycodone and naloxone are present in a weight ratio of from 25:1 to 1:1, preferably 20:1, 15:1 and more preferably 5:1, 4:1,3:1, 2:1 and 1:1.



 

Same patents:

FIELD: medicine.

SUBSTANCE: preparation has pharmaceutical composition containing Oxycodon, Naloxon enclosed into matrix with ethyl cellulose, and the like pharmaceutical composition enclosed into matrix with ethyl cellulose and fatty alcohols being used.

EFFECT: prolonged active ingredients release; high storage stability.

25 cl, 7 dwg, 11 tbl

FIELD: medicine, narcology.

SUBSTANCE: the present innovation deals with treating patients in case of opium (heroin) narcomania due to introducing cytokine-containing immunotropic preparation, moreover, as the above-mentioned preparation it is possible to apply composite solution of cytokines obtained due to arterio-venous perfusion of porcine spleen with physiological solution of sodium chloride at volumetric rate ranged 30-40 ml/min followed by sterilizing filtration and cryoconservation. This solution should be injected intravenously per 200 ml once daily at 3-d-long interval, the course consists of 10-15 infusions after restoring patients' own body weight on finishing the course of curative starvation. Moreover, the course of starvation should be carried out during the period of narcotic abstinence at the background of psychosensory deprivation. The innovation suggested enables to achieve stable refusal of narcotic addiction syndrome due to complex immunocorrection, detoxication and endorphin-like effect.

EFFECT: higher efficiency of therapy.

2 ex

FIELD: medicine.

SUBSTANCE: method involves talking to patient and parents for setting diagnosis. Detoxication, prohibitory and rehabilitative therapy is carried out in hospital. Basic therapy is administered with Clophellinum, Hemineurine, Tizercine, Galoperidol, Loperamide before beginning detoxication. Ultra-rapid opioid detoxication is carried out and vitamin and cardioprotector therapy is applied for 1-2 days after it is finished. Comatose atropine therapy and electric convulsion therapy are alternated every other day at the prohibitory therapy stage. Total number of procedures is equal to 5-6. Ozone therapy is applied every day at the same stage in 80 mg/l mode at a rate of 0.1 l/min. Premedication is carried out before electric convulsion therapy with 0.5 ml of 0.1% atropine sulfate solution, 2 ml of 2% Ditiline solution, 10-15 ml of 20% sodium oxybarbiturate solution. Transcrtanial electric stimulation is carried out at rehabilitation stage. Electric convulsion therapy is carried out once per two-week period during the whole period. Ozone therapy is carried out on the background of anti-depressant introduction twice per 10-14 days.

EFFECT: wide range of functional applications.

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to medicine preparations that are used for treatment of opiomania or opiate dependence being especially heroin dependence. Diamorphine and/or one of pharmaceutically acceptable salts addition of acid are used as active substance. Also, invention relates to a method for treatment of opiate dependence. Invention provides the more long release of an active substance that is not decomposed and not loss activity in storing.

EFFECT: enhanced effectiveness of preparation, valuable medicinal properties.

12 cl, 1 tbl, 2 dwg, 3 ex

The invention relates to oral dosage forms comprising a combination of oral analgesic effective amount of an opioid agonist and orally active opioid antagonist, where the opioid antagonist is included in this ratio to opioid agonist, to obtain a combined product that is effective analgesic when administered orally, but disgusted at physically dependent subject

The invention relates to pharmaceutical

The invention relates to a method of reducing the abuse of an oral dosage form of an opioid analgesic, which analgesic effective amount of orally active opioid agonist is combined with an opioid antagonist in the dosage form for oral administration, and will require at least a two-stage extraction to highlight the opioid agonist and the number entered in the dosage form of an opioid antagonist sufficient to inhibit the action of opioid co-extraction of the opioid agonist and parenteral

The invention relates to pharmacy and medicine and relates to a medicinal product for the treatment of opium addiction

The invention relates to medicine, specifically to the use of certain pyridyl - and pyrimidyl-piperazines, substituted in position 1 of the piperazine ring arylalkyl, aryloxyalkyl or arylthioureas group, is effective in treating diseases caused by the misuse of drugs

FIELD: medicine.

SUBSTANCE: preparation has pharmaceutical composition containing Oxycodon, Naloxon enclosed into matrix with ethyl cellulose, and the like pharmaceutical composition enclosed into matrix with ethyl cellulose and fatty alcohols being used.

EFFECT: prolonged active ingredients release; high storage stability.

25 cl, 7 dwg, 11 tbl

FIELD: medicine, pharmacy, chemical-pharmaceutical industry.

SUBSTANCE: invention relates to a medicinal formulation of tramadol with delayed-release. Proposed medicinal formulation possesses the high effectiveness in treatment of pains of different etiology and can be used in treatment of diseases chosen from the following group: enuresis, cough, inflammatory processes and/or allergic responses, depression states, abuse and/or alcoholism, gastritis, diarrhea, cardiovascular diseases, diseases of respiratory ways, psychic diseases, epilepsy.

EFFECT: improved and valuable medicinal and pharmaceutical properties of formulation.

38 cl, 11 tbl, 4 dwg, 11 ex

FIELD: medicine, pharmacy, chemical-pharmaceutical industry.

SUBSTANCE: invention relates to pharmaceutical salts of the biologically active substance tramadol and at least one sugar substitute chosen from a group comprising saccharin, cyclamate or acesulfam, and a medicament comprising these salts, and its using in treatment of enuresis and pains. The claimed tramadol pharmaceutical salt and sugar substitute possesses the delayed release that provides prolonged curative effect.

EFFECT: improved and valuable medicinal and pharmaceutical properties of salts.

12 cl, 8 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted derivatives of 2-pyridincyclohexane-1,4-diamine of the general formula (I): wherein R1, R2 and R3 mean independently of one another hydrogen atom (H), branched or linear (C1-C8)-alkyl or (C3-C8)-cycloalkyl; R4 means H, branched or linear (C1-C8)-alkyl or -C(X)R7 wherein X means oxygen atom (O); R7 means branched or linear (C1-C8)-alkyl or (C3-C8)-cycloalkyl; R5 means group -CHR11R12, -CHR11-CH2R12, -CHR11-CH-CH2R12, -CHR11CH2-CH2-CH2R12 wherein R11 means H, branched or linear (C1-C7)-alkyl or C(O)O-(C1-C6)-alkyl; R12 means H, (C3-C8)-cycloalkyl or five-membered nitrogen-containing heteroaryl optionally condensed with benzene ring as their racemates or pure stereoisomers being at first enantiomers or diastereomers, and as bases or physiologically compatible acid-additive salts. Compounds of the formula (I) elicit analgesic activity and can be used in medicine.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

15 cl, 1 tbl, 9 ex

FIELD: organic chemistry, medicine, clinical pharmacology.

SUBSTANCE: invention relates to agents used in treatment of pain. Method involves administration to a patient the effective dose of enantiomer of compounds of the formula (Ib) or the formula (IIb) or their mixture. Method provides the antihyperanalgesic effect in acute and chronic pain.

EFFECT: valuable medicinal properties of derivatives.

5 cl, 1 tbl

FIELD: medicine, pharmacy.

SUBSTANCE: invention represents a pharmaceutical tablet comprising a core and bound envelope wherein (a) core comprises solid particles of water-soluble dye dispersed in matrix, and (b) envelope comprises hellanic gum. Due to the presence of water-soluble dye in the tablet core it shows spotted shape that provides easy recognition of the tablet. The tablet is useful for peroral and intraoral administration.

EFFECT: improved and valuable properties of tablet.

30 cl, 6 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new biologically active compounds that are able to modulate the pharmacological response of one or some opioid receptors taken among ORL-1 and μ-receptors. Invention describes a compound of the formula (I): wherein W represents hydrogen atom, (C1-C10)-alkyl, (C1-C4)-alkyl-SO2N(V1)2, cyano-(C1-C10)-alkyl, (C1-C4)-alkyl-CON(V1)2, -NH2-SO2-(C1-C4)-alkyl-, (C1-C4)-alkyl-COOV1 wherein all V1 represent (C1-C6)-alkyl; Q represents a 6-membered aromatic group; n represents a whole number from 0 to 3; n' represents a whole number 0 or 1; A, B and C represent hydrogen atom; Z is taken among the group including a bond, linear or branched (C1-C6)-alkylene; R1 is taken among the group including hydrogen atom, (C1-C10)-alkyl, (C3-C12)-cycloalkyl, (C2-C10)-alkylene, (C3-C12)-cycloalkylamino-group, benzyl, (C3-C12)-cycloalkenyl, monocyclic, bicyclic or tricyclic aryl wherein indicated alkyl, cycloalkyl, alkenyl, (C3-C12)-cycloalkylamino-group or benzyl are optionally substituted with substitutes taken among the group including (C1-C10)-alkyl, phenyl, benzyl, benzyloxy-group wherein indicated phenyl, benzyl and benzyloxy-group are substituted optionally with (C1-C10)-alkyl and indicated (C3-C12)-cycloalkyl, (C3-C12)-cycloalkenyl, monocyclic, bicyclic or tricyclic aryl are substituted optionally with 1-3 substitutes taken among the group including (C1-C10)-alkyl and benzyl wherein indicated benzyl is substituted optionally with (C1-C10)-alkyl; R2 represents hydrogen atom and under condition that when n' = 0 then ZR1 doesn't means hydrogen atom (H), or to its pharmaceutically acceptable salt or solvate. Also, the invention describes a pharmaceutical composition based on thereof. Invention provides preparing new compounds possessing the useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

21 cl, 5 tbl, 8 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes analgesic agent possessing the analgesic effect showing effectiveness against the pain by effect on nociceptors. As an active component the proposed analgesic agent comprises compound represented by the general formula (1) or its salt wherein X, Y, E, Q, A1, A2, R1, R3, R4, R5, R2A, R2C, R2D and R2B re determined in the invention claim.

EFFECT: valuable medicinal properties of agents.

3 tbl, 70 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new substituted indole compounds of Mannich bases of the formula (I):

wherein R1 means hydrogen atom (H), (C1-C10)-alkyl, unsubstituted phenyl or naphthyl bound through (C1-C2)-alkylene group or that monosubstituted at least with hydroxy group (-OH), halogen atom, -CF3, -CN, (C1-C6)-alkyl, (C1-C6)-alkoxy group; R2 means atoms H, F, Cl, Br, groups -CF3, -CN, -OR10, -CO(OR11), -CH2CO(OR12), -COR19, (C1-C10)-alkyl, unsubstituted phenyl or naphthyl, or that monosubstituted at least with -OH, halogen atom, -CF3, -CN, (C1-C6)-alkyl and (C1-C6)-alkoxy group; R3 means -CH(R13)N(R14)(R15); R4, R5, R6 and R7 can have similar or different values and mean atoms H, F, Cl, Br and groups -CF3, -CN, -NO2, -OR10 and others; R10 means H, -COR17, (C1-C6)-alkyl and others; R13 means unsubstituted phenyl or phenyl monosubstituted with at least (C1-C4)-alkyl, halogen atom, -CF3, -CN and -OH; R14 and R15 can have similar or different values and mean unbranched or branched (C1-C6)-alkyl, or R14 and R15 represent in common (CH2)n wherein n means a whole number from 3 to 6, or (CH2)O(CH2)2; R17 means (C1-C6)-alkyl; R19 means -NHR20, (C1-C6)-alkyl and others; R20 means H, (C1-C6)-alkyl and others, and/or their racemates, enantiomers, diastereomers and/or corresponding bases, and/or corresponding salts of physiologically acceptable acids with exception of racemates of some compounds given in claim 1. Also, invention describes method for their preparing and using as a medicinal agent possessing analgesic effect.

EFFECT: valuable medicinal properties of compounds.

42 cl, 2 dwg, 3 tbl, 103 ex

FIELD: medicine, resuscitation.

SUBSTANCE: one should obtain the values on head's vertical position, pulmonary ventilation, efforts coming to organs of controlling and parameters of cabin's hermetic nature. A transport driver should get the information on irregular extreme situation, one should supply 100% oxygen. In case of acute respiratory insufficiency at the background of spontaneous respiration, in case of acute pain, high heart beating or gunshot wound it is necessary to perform additional electrostimulation of the muscles that actively participate in respiration act, with amplitude-frequency-modulated triangular series of impulses at impact duration being 1.5-2.0 sec at pause being about 3-4 sec. Moreover, electrostimulation should be combined with anesthesia performed due to automatic injection of medicinal preparation into biologically active point Tan'-Chzhun along with the intake of therapeutic dosage of an antiaggregant, a thrombolytic, a nitropreparation, beta-adrenoblocking agent and low-molecular heparin. Automatic pharmacoinjection should be conducted manually as a transport driver desired, and in critical situation - due to distance-controlled operation; moreover, injection should be fulfilled perpendicularly for the depth not exceeding 0.5-0.6 cm. The innovation increases the number of preparations applied in extreme situations to rescue a transport driver.

EFFECT: higher efficiency of rescue activity.

3 cl, 1 dwg

FIELD: medicine.

SUBSTANCE: preparation has pharmaceutical composition containing Oxycodon, Naloxon enclosed into matrix with ethyl cellulose, and the like pharmaceutical composition enclosed into matrix with ethyl cellulose and fatty alcohols being used.

EFFECT: prolonged active ingredients release; high storage stability.

25 cl, 7 dwg, 11 tbl

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