Sublingual low-dose opioid tablets and method for preparing them

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a sublingual tablet and a method for preparing it. The sublingual tablet contains an opioid 20 mg/tablet applicable for sublingual application, a directly compressible diluent in the form of an inert core presenting considerably spherical granules containing sucrose and starch. The inert core is covered with at least one active layer containing at least 5 wt % of the inert core of said opioid. A method for preparing the sublingual low-dose opioid tablet involves a stage of producing microgranules by spraying a solution, a suspension or a colloidal dispersion containing said opioid on a surface of the inert core, and compressing the prepared microgranules. The sublingual tablets under the invention have disintegration time making less than 15 min., and fragility making less than 1%.

EFFECT: fast opioid release promotes immediate absorption of the latter in a buccal cavity and fast pain management.

22 cl, 1 dwg, 5 tbl, 3 ex

 

The technical field to which the invention relates.

The present invention relates to pharmaceutical tablets, including low doses of opioid analgesics, as well as the way they are received. Tablets of the invention are particularly useful for sublingual introduction of the above active ingredients.

The present invention also relates to a method for treatment of pain, in which the use of the tablets of the invention.

Prior art

Sublingual introduction has the advantage for the active ingredients in oral administration are significant primary metabolism and enzymatic cleavage when passing through the liver, which leads to a rapid transformation in metabolism and loss of therapeutic activity due to the activity of liver enzymes, which convert the molecule into inactive metabolites, or to loss of activity, which declines as a result of this biological transformation.

Sublingual path reception can lead to the rapid manifestation of action arising due to significant permeability and vascularization intraoral mucosa. In the case of oral administration the tablet is swallowed, and systemic delivery of drugs occurs only at the level of the mucous membrane of the points of the gastrointestinal tract, i.e. later.

In addition, sublingual administration can also ensure that the introduction of active ingredients, which are usually not absorbed at the level of the gastric mucosa or the mucosa of the intestine after oral administration or, alternatively, which are partially or completely dissolved in the acidic environment after swallowing the pills.

Alternative sublingual introduction is transmucosally introduction through the mucous membrane of the cheeks. Fentanyl citrate, an opioid analgesic, is currently available in the form of a Lollipop for transmucosal introduction, which is sold under the brand name Actiq®. The problem with this specific form, is that the patient should keep a Lollipop in your mouth for at least 15 minutes to fentanyl. In addition, the amount of fentanyl absorbed depends on the frequency of swallowing the saliva and thus highly dependent on the individual patient. Thus, it is difficult to strictly control the absorbed amount of fentanyl. And finally, absorption through the mucous membrane of the cheeks is less effective than sublingual absorption.

For this reason, I believe that the unification of opioid analgesics, such as fentanyl, in a composition in the form of sublingual tablets can take advantage of.

Sublingual tablets is etki, known in the prior art, usually obtained by direct compression of a mixture of powders comprising the active ingredient and compression excipient, such as diluents, binders, dezintegriruetsja substances and tools.

In an alternative method of obtaining the active ingredient and compression excipient may previously be subjected to dry or wet granulation.

In this case, the active ingredient is distributed throughout the mass of the tablets.

In patent WO 00/16750 described tablet for sublingual application, which quickly disintegrates and which includes the desired mixture in which the active ingredient is in the form of microparticles attached to the surface of the water-soluble particles, much larger in size and support active microparticles, the composition also includes mucoadhesive tool.

In patent WO 00/57858 described tablet for sublingual application, including the active ingredient, mixed with sparkling system, designed to stimulate the absorption and pH modifier.

Sublingual introduction is a way of introduction, which has certain limitations due to the size of the sublingual cavity, in which is placed a pill; due to the limited amount of saliva in the solution is of the active ingredient, or even because of the limited amount of the active ingredient, which can pass through the mucous membrane of the cheeks.

Because of these limitations tablets in which the active ingredient is evenly distributed throughout the mass of tablets, have certain disadvantages, the resolution of which aimed the present invention.

The first drawback of such tablets in which the active ingredient is distributed throughout the mass, is the dependency that exists between the size of the tablet and the dosage of the active ingredient. Therefore, if you expect to provide tablets with different dosages, you must have the tablets of various sizes.

Therefore, it may happen that the size of the pill that contains the highest dosage, in particular the diameter of the tablets, it is not suitable for sublingual administration.

This may encourage specialists in this field of technology to modify the composition of the tablets containing the highest dose, in particular in such a way as to adapt its size to the sublingual application, which means, ultimately, obtaining tablets with different qualitative and/or quantitative composition of the same active ingredient that is unwanted or economic point of view, nor from the point of view of security.

In addition, sublingual introduction requires the use of the active ingredient with particularly the m particle size, usually consisting of a set in which the diameter is less than 10 μm, preferably less than 5 μm, as measured using various methods, for example, using laser diffraction.

This choice is aimed at ensuring rapid and complete solubilization of the above active ingredient in saliva and to provide immediate and adequate system passing to get an instant effect, which is highly desirable in pain.

At the present time, the use of particles of this size in tablets means that you also need to adapt the particle size of excipients constituting the mass of the tablet, and accurately determine the parameters for mixing powdery mass in order to obtain the desired mixture in which the active ingredient is evenly distributed, without signs of stratification in the loading hopper tablet machines, which could lead to violation of the homogeneity of the contents of the tablets during pressing.

The risk of signs of delamination can be further enhanced, if a single dosage of the active ingredient in each tablet is low. This is, for example, the case of fentanyl, in which the unit dosage is usually smaller than the size from one to several milligrams.

In this case, it is difficult to get PR is integral uniformity of content in the same party throughout the stage of pressing, the active ingredient for the same will be highly diluted in the powder mixture of excipients.

In the case of tablets for sublingual administration, in which the active ingredient is evenly distributed throughout the mass, the release of the active ingredient depends on the speed of disintegration of tablets.

In the prior art described tablets which rapidly disintegrate, which are suitable for sublingual administration, in which the active ingredient is distributed throughout the mass of the tablets.

It is known that these tablets generally have insufficient strength, often less than 40 N, and is characterized by fragility that is so great that they should be treated with caution.

In the case of a tablet having high hardness, disintegration time increases so that the tablet dissolves slowly, releasing the active ingredient at this time begins with the outer surface of the tablet and reaches its kernel.

It is therefore particularly advantageous to have a composition for sublingual administration, which can rapidly release the active ingredient and to provide the opportunity for instant absorption, that such release is not dependent on the speed of disintegration or on the strength of the tablets.

If you conceived that the tablet was subjected to rapid decay and no time is eviane, the disintegration leads to the formation of the adhesive slurry or suspension which may be inadvertently swallowed.

The viscosity of the adhesive slurry or suspension, which is relevant to the application dezintegriruetsja substances or swelling of tools designed to enhance disintegration may cause swallowing reflex.

As a consequence, the fraction of the active ingredient eaten before it is absorbed through the mucous membrane of the cheeks.

The absorption at the level of the buccal mucosa, on which depends biochemist active ingredient, thus, depends on the nature of excipients used in the rapidly disintegrating compositions of this type.

The invention

The applicant has demonstrated that it is possible to correct these shortcomings by using sublingual tablets, including low dosage of the active ingredient that is generated from the microgranules. Tablets of the invention are particularly useful for sublingual introduction of the above active ingredient.

Disclosure of inventions

Sublingual tablet in accordance with the invention includes a directly compressible diluent in the form of an inert core coated with at least one layer comprising a low dosage of the active ingredient (also hereinafter called the "active layer"), and where the active ingredient is an opioid analgesic, suitable for sublingual administration.

In the context of the present invention, the term "inert core" understand mainly of spherical granules comprising sucrose and starch.

The inert core, especially valuable in the context of the invention, includes less than 91.5% of sucrose.

In the present invention successfully used spherical particles, guaranteeing good fluidity and good homogeneity of the mixture intended for tableting.

Excellent rheological properties of the inert cores make it a good candidate as excipients for direct compression. The expiration time of the inert cores under test conditions described in the European Pharmacopoeia, much less than 10 seconds. This property makes possible very efficient loading of tabletting machines. In addition, the inert core has a volume with a very low compactness.

The inert core has the advantage of being directly pressed by exipients, which does not produce dust.

And, finally, the inert core is the time of dissolution, which is less than 15

minutes.

In addition, the present invention makes it possible to eliminate the problem of separation of the mixture, usually observed by direct pressing, since all particles intended for tabletting, have the same size.

The inert core has a size in the range is not 100-2000 μm, preferably 150-600 μm or preferably 150-500 μm, for example, from 180 to 250 μm, or from 400 to 500 μm.

The active ingredients that are useful in the tablet according to the invention are active ingredients that are suitable for buccal or sublingual administration, due to its pharmacokinetic characteristics; in particular, if the active ingredient has a window suction in the cheek, then to the liver needed a way of introducing alternative to the conventional oral route of administration; or alternatively, if you want to get a very quick systemic effect, to overcome the effects of deterioration, such as angina attack, attack, fear, aggravation of allergies, asthma attack, or the attack of the syndrome, caused by, for example, the abolition of opiates or abstinence from alcohol.

Examples of such active ingredients is provided in the publication "rl Mucosal Drug Delivery", Nao Zhang et al., Clin. Pharmacokinet. 2002, 41, (9) 661-680.

In the present invention the active ingredient selected from opioid analgesics suitable for sublingual administration. Examples of opioid analgesics include buprenorphine, norbuprenorphine, fentanyl, methadone, Levorphanol, morphine, hydromorphone, Oxymorphone, codeine, oxycodone, hydrocodone, and their pharmaceutically acceptable salts.

In the present invention fentanyl in the quality of the ve active ingredient means fentanyl and its derivatives.

Derivatives of fentanyl include Alfentanil, Sufentanil and Remifentanil.

The term "pharmaceutically acceptable salt" means derivatives of the disclosed compounds in which the basic pharmaceutically active compound is transformed into its salt with a base or acid; examples of pharmaceutically active salts include, in particular, salts of organic and inorganic acids with basic residues such as amines, salts derived from alkali metals or organic salts of acidic residues such as residues of carboxylic acids, etc.

Examples of pharmaceutically acceptable salts include fentanyl fentanyl citrate and fentanyl hydrochloride. Examples of pharmaceutically acceptable salts of the derivatives of fentanyl include Alfentanil hydrochloride, Sufentanil citrate and Remifentanil hydrochloride.

Preferred active ingredients are fentanyl in the basic form of fentanyl citrate, Alfentanil, Alfentanil hydrochloride, Sufentanil, Sufentanil citrate, Remifentanil, Remifentanil hydrochloride.

The active ingredients can be applied in any polymorphic form, in racemic form or in the form of their enantiomers or mixtures of enantiomers.

The active ingredient may be in powder form, for example, fine powder or micro-crystals.

The number of sports the ingredient is preferably less than 20 mg/tablet more preferably less than 10 mg/tablet, for example, from 0.1 to 10 mg/tablet, preferably from 0.1 to 2 mg/tablet. The amount of active ingredient regulate within the above boundaries in accordance with the type of the active ingredient.

Provided that the tablets are tablets with a low dosage, is usually not necessary to add additional excipient in the composition of the covering shell (also hereinafter called the "active layer")comprising the active ingredient, applied over an inert core. The microspheres are preferably composed of an inert core, the surface of which is adsorbed active ingredient.

In the preferred embodiment, the active layer is devoid of any exipients.

If, despite everything, it is proved that eccipienti are preferred for the deposition of the active layer on the inert core, choice of appropriate composition and the amount will be such that they are not modified significantly the ability of the inert cores to form tablets or not modified release of the active ingredient.

Pharmaceutically acceptable exipient not necessarily present in the active layer are selected from binders, soluble substances, surface-active substances, stimulants, suction, bioadhesive agents, antistatics, the N-modifiers acid-base pairs, which cause the liberation of gas bubbles, sweeteners, flavorings, colorants and mixtures thereof.

The binder, which is optionally present in the active layer, used in proportions which can reach up to 95% by weight relative to the dry mass of the shell, preferably up to 30% by weight relative to the dry mass of the active layer.

His role involves the binding of the active ingredient with an inert core without loss of substance or in the formation of a homogeneous layer of the active ingredient and other excipients, evenly distributed around the inert core.

The binder is preferably selected from polymers which are hydrophilic and/or soluble at the pH of saliva to ensure the immediate release of the active ingredient; such as polyvinylpyrrolidone and polymers based on cellulose, acrylic polymers are the polyethylene glycols.

Polyvinylpyrrolidone can be selected from polymers having a molecular weight in the range from 10000 to 50000.

The polymer based on cellulose is chosen from hydroxylated derivatives, for example, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, phthalate of hydroxypropylmethylcellulose and acetolactate hydroxypropylmethylcellulose.

Preferred GI is oksipropilmetiltselljuloza selected from compounds whose apparent viscosity (water solution with a concentration of 2% wt./mass. at 20°C, USP method) ranges from 2.4 to 18 JV and even more preferably from 2.4 to 5 SP.

The preferred polyethylene glycol is selected from compounds that have the calculated molecular weight is 4000 or 6000 g/mol.

Soluble substance which may not be present in the active layer, used in proportions which can reach up to 90% by weight, preferably from 1% to 60% and even more preferably from 30 to 60% by weight, calculated with respect to the dry mass of the active layer.

Such soluble substance is used, in particular, to improve the solubilization of the active ingredient with increasing solubilize membranes, including the active ingredient.

Soluble substance can be selected from the group of sugars, such as sucrose, lactose or dextrose; polyols, such as mannitol, sorbitol or lactitol; or else from inorganic salts such as sodium chloride.

Surfactant, which is optionally present in the active layer can be selected from cationic, anionic, nonionic or amphoteric substances by themselves or in a mixture.

Surfactant can be selected, for example, from compounds such as sodium laurylsulfate, monooleate, monolaurate, monop imitat, the monostearate, Triolet, tristearate or any other ester polyoxyethylenated sorbitan, preferably Tween® 20, 40, 60 or 80; glycerides polyoxyethylenated fatty acids, these fatty acids are saturated or unsaturated and consist of at least 8 carbon atoms; poloxamer, such as poloxamer 188, ethylene oxide/propyleneoxide block copolymers, such as Pluronic® F68 or F87; lecithin, stearyl alcohol, clearily alcohol, cholesterol, polyoxyethylenated castor oil, polyoxyethylene esters of fatty alcohols, such as products Brij® and polyoxyethylene stearates.

Surfactant predominantly present in proportions which can go up to 20%, preferably from 0.1 to 20% by weight relative to the total dry mass of the active layer.

Amplifiers suction, which are not necessarily present in the active layer, are compounds that make it possible to improve the absorption of the active ingredient through the walls of the buccal cavity into the bloodstream.

These compounds can be selected from the group including, for example, sodium laurylsulfate, sodium capret or chitosans, as well as inhibitors of P-glycoprotein (P-gp), such as Polysorbate 80, Cremophor® EL (hydrogenated castor oil) or SolutolitHS-15 (PEG-HS or 12-hydro is distearate peg-660).

Bioadhesive tools that are not necessarily present in the active layer can be selected from the group including, for example, carbomer, sodium carboxymethyl cellulose, sodium alginate, hypromellose, hydroxypropylcellulose, hydroxyethyl cellulose, ethylcellulose, gelatin, guar gum, polyethylene oxides (trademark Polyox®) and dextran.

The antistatic agent, which is optionally present in the active layer can be selected from the group consisting of colloidal silica, preferably precipitated silica, micronized talc, and mixtures thereof.

The antistatic agent is used in proportions which may reach 60% by weight, calculated with respect to the dry mass of the shell caused around the compressed core.

Acidic/basic pair, causing the liberation of gas bubbles, which are not necessarily present in the active layer is formed of alkaline agents and acidic substance, which is selected from pharmaceutically acceptable compounds so that in the presence of water they provided the gas.

The advantage of applying the mixture, causing the liberation of gas bubbles in a casing, comprising the active ingredient, is to facilitate rapid dissolution of the active layer formed around the microgranules, after contact with solunas; and thus, by releasing the pharmaceutically acceptable gas and induction of local changes of pH in the buccal cavity is due to the rapid dissolution of the active ingredient on the buccal or sublingual mucous membranes, and improved systemic delivery of drugs, and at the same time improves the organoleptic properties so that in the buccal cavity is less than the presence of the active ingredient or there is a pleasant subacid flavor.

The acid agent is a compound, dosing protons, which reacts with the alkaline medium so that the formation of gas, which induces the release of bubbles in a liquid in which the gas is released.

Acid means may consist of any inorganic or organic acid in the form of the free acid, acid anhydride or acid salt.

This acid is chosen from the group including, in particular, tartaric acid, citric acid, maleic acid, fumaric acid, malic acid, adipic acid, succinic acid, lactic acid, glycolic acid, alpha hydroxy acids, ascorbic acid and amino acids as well as salts and derivatives of these acids.

Alkaline comprises compounds capable of forming gas in the reaction the AI connection, dosing protons. Formed gas is carbon dioxide, oxygen or any other type of biocompatible gas.

The alkaline agent is chosen from the group comprising potassium carbonate, lithium carbonate, sodium carbonate, calcium carbonate, ammonium carbonate, L-lysine carbonate, arginine carbonate, sodium glycine carbonate, sodium carbonate amino acids, anhydrous sodium perborate, fizzy perborate, sodium perborate monohydrate, sodium percarbonate, sodium dichloroisocyanurate, sodium hypochlorite, calcium hypochlorite, and mixtures thereof.

In the context of the present invention, the term "carbonate" means, without exception, carbonates, sesquicarbonate and bicarbonates.

The appropriate amount of acidic substance and alkaline agents are selected so that the reaction between the alkaline agent and the protons released from the acid, would be the formation of a sufficient amount of gas to achieve a satisfactory allocation of bubbles.

Acid tool itself or alkaline tool itself can be used to adapt the amount in the envelope to ensure that the active ingredient was located mainly under the main form, i.e., the absorbed fraction.

Suitable sweeteners that are not necessarily present in the active layer is, you can choose from a group including, in particular, aspartame, Acesulfame potassium, sodium saccharinate, neohesperidoside, Sucralose, monoamine the glycyrrhizinate, and mixtures thereof.

Suitable flavoring agents and dyes, which are not necessarily present in the active layer, are substances commonly used in the pharmaceutical industry to obtain tablets.

The inclusion of a sweetener (sweeteners and/or flavors in the shell inert cores of the present invention is particularly useful in order to mask the bitterness of some of the active ingredients.

Dyes are substances that are commonly used in the pharmaceutical industry. The dye is used in a proportion, which can reach up to 1% by weight, calculated with respect to the dry mass layer applied around the inert core.

In a specific embodiment, the active layer does not include any sweeteners or flavorings.

The composition of excipients in the active layer are selected so that the active ingredient is completely dissolved in the dissolution of the tablets.

The inert core comprising an active layer (called hereinafter "active core"), may not necessarily be covered by a layer comprising a pH-modifying compound, the layer is called pH-modifying layer.

In accordance with one waples is of pH-modifying layer may be located above or below the active layer.

In accordance with another embodiment of the pH-modifying compound can be in the active layer.

If the tablet is placed in the buccal cavity, the pH-modifying layer provides local alkaline or acidic pH, which enhances the absorption of the active ingredient mucous membrane.

Suitable pH-modifying compounds include citric acid and sodium citrate or potassium citrate, sodium hydroxide, monoethanolamine, diethanolamine, sodium bicarbonate or potassium bicarbonate, sodium phosphate, tartaric acid, propionic acid, lactic acid, malic acid and monosodium salt of glutamate.

The choice of the pH-modifying compound depends on the nature of the applied active ingredient. If the absorption of the active ingredient mucous membrane of the cheeks increases in alkaline conditions, as the pH-modifying compound used alkaline compound. If the absorption of the active ingredient mucous membrane of the cheeks is enhanced in acidic conditions, as the pH-modifying compound used acid connection.

The composition of the pH-modifying layer are selected so that the active ingredient is completely dissolved upon contact with saliva, the pH value in the buccal region picked so that it would benefit from blingbling absorption of the active ingredient.

In the pH-modifying layer is optional, you can turn eccipienti identical to those found in the active layer.

In the case of fentanyl as active ingredient an optimal pH-modifying layer is an alkaline layer comprising an alkaline compound.

In accordance with one embodiment of alkaline covering layer may be placed over or under the layer of fentanyl.

In accordance with another embodiment of the alkaline compound can be inside layer of fentanyl.

If the tablet is placed in the buccal cavity, the above alkaline layer provides local alkaline pH, which enhances the absorption of fentanyl mucous membrane.

Alkaline optional layer may include eccipienti, identical to those that are in the layer, including fentanyl.

Alkaline compound mainly chosen from the group comprising Tris, tartrate, acetate, phosphate, and preferably anhydrous disodium phosphate salt, and mixtures thereof.

The invention also relates to a method for inert core tablet of the invention.

This method includes applying an active layer on the inert core by spraying of a solution, suspension or colloidal dispersion comprising the active ingredient, suitable for sublingual administration and, optionally, at the ore, one pharmaceutically acceptable excipient on the surface of the inert core.

Active ingredients and excipient are those substances which have been described above and which are relevant to the tablet of the invention.

In the preferred embodiment the active ingredient is a fentanyl or its pharmaceutically acceptable salt in any polymorphic form, in racemic or enantiomeric form.

The active layer is evenly distributed over the surface of the inert microgranules.

In particular, for water-insoluble substances it is possible to create a layer in which the active ingredient is in the form of a solid dispersion obtained by coprecipitation active ingredient with a hydrophilic polymer.

Spraying can be carried out in a perforated drum or in the installation for applying liquid coatings. In the preferred embodiment, the dispersion of the active layer on the surface of the inert micro granules is carried out in the perforated drum, in particular in the perforated drum having a section with a triangular profiles are parallel to each other and defining the size of the slot between them, such as have been described in patent application EP 1044064.

Composition to obtain the shell is sprayed in the form of a solution, suspension or colloidal dispersion in an organic or aqueous solvent, or a mixture thereof is then dried.

The organic solvent may be selected from ethanol, isopropanol, tetrahydrofuran, simple isopropyl ether, acetone, methyl ethyl ketone, dichloromethane or mixtures of these solvents.

Purified water is a solvent used preferably in the case, if the shell does not contain effervescent funds; on the other hand, it is necessary to use an organic solvent, if sprayed, the composition comprises a pair of acid/base, which induces the release of gas bubbles.

In one embodiment of the method of obtaining the inert core includes a step of applying a pH-modifying layer on the specified kernel, preferably by spraying of a solution, suspension or colloidal dispersion, comprising the pH-modifying compound and optionally at least one pharmaceutically acceptable excipient on an inert core.

If the active ingredient is a fentanyl or its pharmaceutically acceptable salt, pH-modifying compound is an alkaline compound and a pH-modifying layer is an alkaline layer.

You can apply the pH-modifying layer simultaneously with the active layer or can be applied over or under the active layer.

The dispersion pH-modifying layer can be, for example, in the perforated drum Il is in the installation for applying liquid coatings. In the preferred embodiment the spray pH-modifying layer on the surface of the inert core is carried out in the perforated drum, in particular in the perforated drum having a section with a triangular profiles are parallel to each other and defining the size of the slot between them, such as have been described in patent application EP 1044064.

The choice of equipment makes it possible to control the application of pH-modifying layer and to prevent any signs of clumping associated with the nature of the active ingredient and excipients pH-modifying composition to obtain a shell with a different style parameters (temperature, pressure, flow rate of solution).

Composition to obtain a membrane containing the pH-modifying compound is applied in the form of a solution, suspension or colloidal dispersion in an organic or aqueous solvent, or mixtures thereof, and then dried.

The number of binders shall be chosen in accordance with the nature and amount of active ingredient sprayed over the inert core.

In particular, for water-insoluble substances, you can create a layer in which the active ingredient is present in the form of a solid dispersion obtained by coprecipitation active ingredient with a hydrophilic polymer.

The solvent used is La coating, will typically be water or any other permitted solvent with an appropriate level of dryness.

Purified water is a solvent used preferably in the case, if the coating does not contain effervescent funds; on the other hand, it is necessary to use an organic solvent, if sprayed, the composition comprises a pair of acid/base, which induces the release of gas bubbles.

The organic solvent may be selected from ethanol, isopropanol, tetrahydrofuran, simple isopropyl ether, acetone, methyl ethyl ketone, dichloromethane or mixtures of these solvents.

Sublingual tablet of the invention can be obtained by using a method including at least the following stages:

1) preparation of microgranules comprising a layer comprising the active ingredient, by spraying the solution or suspension comprising the active ingredient, suitable for sublingual administration and, optionally, at least one pharmaceutically acceptable excipient, on an inert core; and

2) pressing the microgranules obtained in stage 1, to obtain tablets.

In one embodiment of stage 1 of the method of producing tablets of the invention involves the step of applying a pH-modifying layer on the specified kernel.

The method of the invention is advantageous from the point of view of security the spine, as it eliminates the manipulation of the active ingredients in the form of powder mixtures, as it happens in traditional stages of granulation and/or pressing, and allows that the product was made with the help of the active ingredient in the form of a sprayable solution or suspension.

Especially valuable in the case of highly toxic active ingredients will be, if the method of the invention eliminates the handling of these substances in the form of powder mixtures, as it happens in traditional stages of granulation and/or pressing, and allows you to highly toxic active ingredient was prepared by using the active ingredient in the form of a sprayable solution or suspension.

Conditions and detailed information about stage 1 in the method of producing tablets of the invention are the same as those described above regarding the method of obtaining the inert core of the invention.

Not necessarily at the stage of pressing the microgranules obtained in stage 1, you can add sliding substances.

These sliding substances can be present in an amount which is less than 1% by weight relative to the weight of the tablet, preferably in the range of 0.10 to 0.75% by weight, more preferably of the order of 0.10% - 0,50% by weight of the tablet.

Moving the substance makes it possible to reduce the friction between particles and between particles and mold the th. It also reduces the adhesion of particles to punch presses and achieve brilliance. Moving the substance chosen from, for example, magnesium, zinc or calcium stearate, talc, Aerosil®, stearic acid, sodium fumarate and PEGs.

Sublingual tablets of the present invention demonstrate the homogeneity of the mass, which is significantly less than 5% and about 1% for tablets with a weight of about 300 to 500 mg; brittle, constituting less than 1%; the time of dissolution at 37°C less than 15 minutes and the strength of the order of from 0 to 200 N. These parameters can be adjusted by changing parameters tableting.

Beneficial to the compression force applied in stage 2, ranged from 5 to 50 kN, if the area of the compression surface is 1 cm2(for example, from 50 to 500 MPa), preferably from 10 to 30 kN. The compression force of adjusted so as to obtain the tablet strength is measured in accordance with the method of the European Pharmacopoeia (2.9.8) is preferably from 10 to 180 N, more preferably from 15 to 100 N.

Preferably the strength of the tablets of the invention adjusted so as to obtain fragility, measured in accordance with the method of the European Pharmacopoeia, part 1 mass%.

The advantage of tablets in accordance with the invention is that they have time disinteg the purpose, in less than 15 minutes, preferably from 5 to 15 minutes

The disintegration time was measured in vivo by placing the coated tablets, sublingual cavity, and measuring with a stopwatch the time that passes between the start of measurement and the time when the film-coated tablet, completely decompose under the action of saliva and without grinding, thus to form a sticky substance, the patient all this time should not take any action in the oral cavity.

Tablets of the invention can have a diameter of from 2 to 14 mm and have a round, oval, oblong or other shape may be flat, convex, or other surface, and optionally may have a notch.

Preferably, the tablets of the invention are round biconvex shape, which is advantageous form, as for tabletting process and contact film-coated tablets, with the saliva, if the specified tablet is placed in the buccal cavity.

In accordance with a specific embodiment of sublingual tablets in accordance with the invention can be covered with a film, or to improve their appearance, or to mask the color, or to protect the active ingredient from light, moisture or atmospheric oxygen.

In accordance with another embodiment of the invention, the can is about to apply painting means in the shell tablet for marking, indicate the type and dosage of the active ingredient. Indeed, whatever the dosage, the size of the tablets can be one and the same. In order to distinguish between different dosages, with a specific dosage may be associated with a specific color.

In a particularly useful embodiment of the method of obtaining sublingual tablets in accordance with the invention includes at least the following stages:

1) preparation of microgranules comprising an opioid analgesic suitable for sublingual administration, preferably fentanyl as active ingredient, and, optionally pharmaceutically acceptable excipient, on the surface of the inert core; and

2) pressing the microgranules obtained in stage 1, optionally together with a moving substance, to obtain, thus, tablets;

where the term "fentanyl" should be understood as described above.

Conditions and detailed information about stages 1 and 2 of this embodiment are the same as those described above regarding the method of producing tablets in accordance with the invention.

Optional way to obtain tablets of the invention includes spraying the solution or suspension also comprising an alkaline compound, to the surface of the inert core. Above the stage can be performed directly on the surface of the inert cores (p the ed stage 1) or simultaneously with the stage atomization shell, containing the active ingredient (simultaneously with stage 1), or on the surface of the active nucleus, obtained in stage 1.

In accordance with a specific option sublingual tablets containing fentanyl, in accordance with the invention can be covered with a film, or to improve their appearance, or to mask the color, or to protect the active ingredient from light, moisture or atmospheric oxygen.

The present invention is also directed to a premix for tableting, which consists of a composition containing from 99 to 100% by weight of the inert core coated with at least one active layer comprising a low dosage of opioid analgesic suitable for sublingual administration and from 0 to 1% by weight of the moving substance. This composition is intended for direct compression.

The core is coated from a premix for tableting in accordance with the invention may include a pH-modifying layer described in this document relating to the inert core comprising an active layer, and to receive his blessing.

The active ingredient preferably represents less than 5% by weight of the inert core.

In the preferred embodiment of the opioid analgesic is a fentanyl, where the term "fentanyl" shall mean the term op is edeleny above.

The present invention is also directed to a method of obtaining sublingual tablets of the invention using direct pressing of the above premix for tableting. In accordance with this method, the compression force is preferably from 5 to 50 kN, if the surface area of the pressing is 1 cm2(for example, from 50 to 500 MPa), preferably from 10 to 30 kN.

In addition, the present invention relates to a method of treatment of pain, which includes the introduction in the buccal cavity of a patient a therapeutically effective amount of the active ingredient in the form of sublingual tablets, where the active ingredient is chosen from the group comprising opioid analgesics suitable for sublingual administration, such as buprenorphine, norbuprenorphine, fentanyl, Alfentanil, Sufentanil, Remifentanil, methadone, Levorphanol, morphine, hydromorphone, Oxymorphone codeine, oxycodone, hydrocodone, and their pharmaceutically acceptable salts.

Particularly preferred active ingredients are fentanyl, fentanyl citrate, Alfentanil, Alfentanil hydrochloride, Sufentanil, Sufentanil citrate, Remifentanil, Remifentanil hydrochloride.

In a particularly useful embodiment of the method of treatment of pain in accordance with the present invention includes the introduction in the buccal cavity of the patient terapeuticas the effective number sublingual tablets including directly compressible diluent in the form of an inert core coated with a low dosage of fentanyl as active ingredient, where the term "fentanyl" is understood as the term is defined above.

A method of treating pain in accordance with the present invention is particularly useful in the treatment of paroxysmal pain, particularly paroxysmal pain in cancer. It is particularly suitable for the treatment of patients who have received therapy with opioids and are not susceptible to treatment with opioids their main stable of pain.

Patients who are considered tolerant to opioids, are those patients who receive at least 60 mg morphine/day, at least 25 mg transdermal fentanyl/hour, at least 30 mg of oxycodone daily, at least 8 mg of oral hydromorphone daily, or an equivalent analgesic dose of another opioid for a week or longer.

The invention also relates to the use of opioid analgesic suitable for sublingual administration, such as buprenorphine, norbuprenorphine, fentanyl, Alfentanil, Sufentanil, Remifentanil, methadone, Levorphanol, morphine, hydromorphone, Oxymorphone codeine, oxycodone, hydrocodone and pharmaceutically acceptable salts, for the manufacture of sublingual tablets in accordance with the invention is.

Fentanyl and its derivatives in any polymorphic form, in racemic form or in the form of their enantiomers or in the form of mixtures of enantiomers, in basic form or in the form of pharmaceutically acceptable salts are preferred active principle. Particularly preferred active principle is a fentanyl, fentanyl citrate, Alfentanil, Alfentanil hydrochloride, Sufentanil, Sufentanil citrate, Remifentanil, Remifentanil hydrochloride.

Sublingual tablets thus obtained in accordance with the invention, is particularly useful for the treatment of paroxysmal pain, particularly paroxysmal pain in cancer. It is particularly suitable for the treatment of patients who have received therapy with opioids and are not susceptible to treatment with opioids their main stable of pain.

The invention will be clearer from the following examples which, however, do not limit the scope this invention.

Information confirming the possibility of carrying out the invention

The following examples used the above products: Inert core "Neutres SP" (400 - 500 μm), commercially available from the company "NPPHARM".

The inert core "NPTAB 200" (180 - 250 μm), commercially available from the company "NPPHARM".

A receiver array 603 (hypromellose), commercially available under the trade titled the m Pharmacoat 603 " company "Shin-Etsu".

PEG 6000, commercially available under the trade name "Renex PEG 6000" company "Quimasso".

Magnesium stearate, commercially available from the company "Quimdis".

Presents the percentages are expressed in wt./mass. percent.

Example 1

1 - Coating the inert core

The solution of fentanyl citrate and PEG 6000 in water for coating is sprayed into the installation for applying liquid coatings to the surface of 1000 g of inert core SP. Formula granules, coated, are presented in table 1.

Table 1
SubstanceThe composition of the party (g)% composition
The inert core SP1000,098,54
Fentanyl citrate1,30,13
PEG 600013,51,33
Water167,5-
Total (dry mass)1014,8100

2 - Lubrication and pressing

Microspheres coated grease using 0.2% of magnesium stearate.

The microspheres are then pressed on alternative press (Frogerais OA), are equipped with a flat round perforations with beveled edge, diameter 11 mm

The obtained tablets in accordance with the invention contain a single dosage, component 0,63 mg of fentanyl citrate, i.e. 0.4 mg of fentanyl in the main form.

Example 2

1 - Coating the inert core fentanyl citrate

The solution of fentanyl citrate and receiver array 603 in water for coating is sprayed into the fluidized air layer on the surface of 700 g of inert cores NPTAB 200. Formula granules, coated, are presented in table 2.

Table 2
SubstanceThe composition of the party (g)% composition
The inert core NPTAB 200700,096,34
Fentanyl citrate6,30,87
A receiver array 60320,02,79
Purified water581,0-
Total (dry mass) 167,5100

2 - Lubrication and pressing

Microspheres coated grease using 0,22% magnesium stearate.

The microspheres are then pressed on alternative press (SVIAC PR12), has a circular convex perforations with a diameter of 5.5 mm

The composition of the tablets in accordance with the invention are shown in table 3.

Table 3
SubstanceThe composition of the party (g)% composition
NPTAB 200 covered fentanyl citrate970,0efficiency of 99.78
Magnesium stearate2,170,22
Only972,17100

The obtained tablets in accordance with the invention contain a single dosage, component 0,63 mg of fentanyl citrate, i.e. 0.4 mg of fentanyl in the main form.

Example 3

In healthy volunteers-men conducted a cross-comparative study of biochemisty single doses of tablets prepared in accordance with example 2, in comparison with Actiq® number 04 mg in terms of food restrictions.

The purpose of this pilot study was to evaluate the relative biochemisty a single dose of both compositions in healthy volunteers-men in terms of food restrictions.

The tablets obtained in accordance with example 2, and the product selected for comparison, was administered to 10 patients and measured values of Cmax, tm and AUC.

The product selected for comparison, is a composition of fentanyl citrate (solid drug matrix on a stick), designed to facilitate transmucosal suction, and widespread under the brand name Actiq®.

As the invention, and a product designed for comparison, contain fentanyl citrate in an amount equivalent to 0.4 mg of fentanyl in the main form.

Blood samples: before the dose and at the appropriate time after each stage: 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 75, 90 minutes and 2, 3, 4, 6, 8, 12 and 24 hours after dose.

The pharmacokinetic parameters AUC 0-t, AUC, Cmax, and tmax were calculated for fentanyl in plasma.

The average geometric values are presented in table 4:

Table 4
Parameter (CV%)Invention (n=10)Actiq® 0.4 mg(n=10)
AUC 0-t (PG·h/ml)3526,80(22,5%)3059,25(33,1%)
AUC(PG·h/ml)4079,90(28,8%)3473,98(37,0%)
Cmax (PG/ml)491,67(29,4%)406,614(27,1%)
tmax*(h)2,52,0
[0,42-3,00][1,0-3,0]

*median [range]

The average attitude of the invention relative to Actiq® calculated in table 5 below.

Table 5
The invention relative to Actiq®
AUC 0-tto 110.7
AUC112,6
Cmax 113,5

Results are also presented in figure 1.

The invention demonstrates similar biouswoyaemosti and Cmax, and Actiq®.

1. Sublingual tablet, with less than 20 mg/tablet opioid analgesic suitable for sublingual administration, directly compressible diluent in the form of an inert core, which consists mainly of spherical granules comprising sucrose and starch coated with at least one active layer comprising less than 5% by weight of the inert cores specified opioid analgesic suitable for sublingual administration.

2. Sublingual tablet according to claim 1, where an opioid analgesic is selected from the group consisting of buprenorphine, norbuprenorphine, fentanyl, methadone, Levorphanol, morphine, hydromorphone, Oxymorphone codeine, oxycodone, hydrocodone and pharmaceutically acceptable salts in any polymorphic form, in racemic or enantiomeric form.

3. Sublingual tablet according to claim 1, where an opioid analgesic is selected from the group consisting of fentanyl in the basic form of fentanyl citrate, Alfentanil, Alfentanil hydrochloride, Sufentanil, Sufentanil citrate, Remifentanil and Remifentanil hydrochloride.

4. Sublingual tablet according to claim 1, where the active layer does not contain exipient.

5. Sublingual tablet according to claim 1 where the inert core is open pH-modifying layer.

6. Sublingual tablet according to claim 3, where the inert core coated by alkaline layer.

7. Sublingual tablet according to claim 1, where the size of the inert core ranges from 100 to 2000 μm, preferably from 200 to 600 μm, more preferably from 200 to 400 microns.

8. Sublingual tablet according to claim 1, having a strength of from 0 to 200 N.

9. Sublingual tablet according to claim 1, having a brittle from 0 to 1%.

10. Sublingual tablet according to claim 1, having a disintegration time of less than 15 minutes

11. Sublingual tablet according to claim 1, where the tablet further includes one or more lubrication in number, constituting less than 1% by weight relative to the weight of the tablet, preferably from 0.125 to 0.75% by weight relative to the weight of the tablet, more preferably about 0.25% by weight relative to the weight of the tablets.

12. Sublingual tablet according to claim 1, where the amount of active ingredient is less than 5 mg/tablet.

13. A method of obtaining a sublingual tablet according to claim 1, comprising at least the following stages:
(1) preparation of microgranules comprising an opioid analgesic suitable for sublingual administration, by spraying of a solution, suspension or colloidal dispersion, comprising the specified opioid analgesic suitable for sublingual administration, on the surface of the inert core; and
(2) pressing the microgranules obtained is in stage 1, to obtain sublingual tablets.

14. The method according to item 13, where the solution, suspension or colloidal dispersion, comprising the specified opioid analgesic suitable for sublingual administration, contains no exipient.

15. The method according to item 13, where the solution, suspension or colloidal dispersion, comprising the specified opioid analgesic suitable for sublingual administration, further includes at least one pharmaceutically acceptable excipient.

16. The method according to item 13, where the specified opioid analgesic selected from the group consisting of buprenorphine, norbuprenorphine, fentanyl, methadone, Levorphanol, morphine, hydromorphone, Oxymorphone codeine, oxycodone, hydrocodone and pharmaceutically acceptable salts in any polymorphic form, in racemic or enantiomeric form.

17. The method according to item 13, where the specified opioid analgesic selected from the group consisting of fentanyl in the basic form of fentanyl citrate, Alfentanil, Alfentanil hydrochloride, Sufentanil, Sufentanil citrate, Remifentanil, Remifentanil hydrochloride.

18. The method according to 17, where stage 1 additionally includes a step of applying an alkaline layer.

19. The method according to item 13, where stage 1 additionally includes a step of applying a pH-modifying layer.

20. Microgranule comprising an inert core, which consists mainly of pricesbuy granule, including sucrose and starch coated with at least one active layer comprising less than 5% by weight of the inert cores specified opioid analgesic suitable for sublingual administration.

21. Sublingual tablet according to claim 1 for the treatment of pain, such as paroxysmal pain, particularly paroxysmal pain in cancer.

22. Sublingual tablet according to item 21 for the treatment of pain in a patient who is already undergoing treatment with opioids.



 

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15 cl, 8 dwg, 4 tbl, 7 ex

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