The composition of fentanyl for the treatment of acute pain

 

Described pharmaceutical composition for the treatment of acute pain by sublingual administration. The composition comprises, essentially anhydrous mixture of microparticles of fentanyl or its pharmaceutically acceptable salt and agent, reinforcing bioadhesion and/or mucoadhesive. Microparticles of fentanyl attached to the surface of the particle carrier. The particles of the medium more particles of fentanyl, are substantially water soluble and have an average diameter of less than 750 μm. The invention also relates to a method for treatment of acute pain by the sublingual introduction of specified pharmaceutical composition. The use of the new composition allows you to enter a small amount of fentanyl, which reduces the risk of side effects in the body of the patient, as well as the variability in therapeutic response among patients. 2 N. and 17 C.p. f-crystals, 1 Il., 1 PL.

This invention relates to a quickly dezintegriruetsja pharmaceutical composition for sublingual administration fentanyl for the treatment of acute pain and to a method of production of the relevant medicinal product.

Acute and/or severe pain is a common reason for emergency treatment and hospitalization. In the case of cancer of the AMI, as such or in combinations. Requiring opioid for cancer patients suffering from pain, usually slow-release opiates (slow-release morphine or Ketobemidone, or fentanyl for percutaneous introduction). A characteristic feature of cancer pain are periods of inadequate analgesia (intermittent pain). Most often the pain is due to increased physical activity of patients. However, the treatment of intermittent pain introduction for a long time uneven doses of long-acting analgesics causing adverse side effects such as excessive sedation, nausea, constipation. Currently available oral, rectal or sublingual pain medication are characterized by a relatively extended period commencement or uncertain absorption properties that are not well suited to address acute or intermittent pain.

The operating state of acute/post-operative or traumatic/post-traumatic pain, and pain due to severe disease (eg, myocardial infarction, renal stone disease, and so forth) are usually treated with opioid analgesics, which impose PA is the major. In such cases, start to act quickly oral alternatives are of great therapeutic interest.

Fentanyl, N-(1-phenethyl-4-piperidyl)-propionanilide, is an opioid agonist and has many pharmacological effects of opiates such as morphine and meperidine. However, compared to these opiates fentanyl has less sedative effect, rarely causes the secretion of histamine and respiratory depression appears to be more short-lived. Fentanyl commercially available for intravenous, vnutrimyshechnogo (bread for transmucosal introduction) and percutaneous injection.

After injecting fentanyl analgesic action is faster and less prolonged than morphine and meperidine. After intravenous analgesic action begins quickly. Peak analgesia is achieved within a few minutes. After rassechennogo introduction using pellet suction cakes usually completed within 30 minutes and peak plasma concentration is reached after about 20 min, as described, for example, Farrar et al., J. Natl. Cancer Inst., 1998, 90(8), p.611-616. Analgesic effect appears after 5-15 minutes, and peaks approximately 20-50 minutes Although the rapid onset of anesthesia will be much better for the patient. In addition, a significant number of input with pellet fentanyl eaten by the patient. This is not desirable and leads to the introduction of excessive quantities of drugs that may cause increased side effects.

Fentanyl has toxic potential of opiate agonists, and should be observed in this area precaution. Respiratory depression is the most serious adverse phenomenon occurring after buccal, parenteral, and transdermal administration. Patients receiving fentanyl transmucosal, facial flushing, and itching are normal phenomena. Nausea and vomiting also appear quite often after buccal therapy.

One aspect of the invention is the provision of treatment of acute or intermittent pain by oral administration of fentanyl way, leading to increased pharmacologically effective levels of fentanyl in plasma within a short period of time after injection.

In another aspect of the invention provides a pharmaceutical composition suitable for this purpose.

Another aspect of the invention relates to a method of creating such a composition.

In an additional aspect of the image is Biologicheskie effective dose of fentanyl, used for the treatment of acute pain.

The drawing shows the results of a study of the biological availability of the active agent in the composition according to the invention is a diagram showing changes in the concentration of agent in the plasma depending on the time.

According to the invention for oral treatment of acute or intermittent pain includes sublingual prescribed a mixture containing a pharmacologically effective amount of fentanyl or one or more of its pharmaceutically acceptable salts. In a preferred aspect of fentanyl or one or more of its pharmaceutically acceptable salts is administered sublingual in combination with the connection, reinforcing bioadhesion and/or mucoadhesive.

According to the invention also contemplates a single dose pharmaceutical composition for sublingual administration, containing a pharmacologically effective amount of fentanyl or one or more of its pharmaceutically acceptable salts. In a preferred aspect of the above composition also contains a compound that strengthens bioadhesion or mucoadhesive. This arrangement reduces the possibility of absorption of indeterminate amount of drug swallowed with the saliva of the patient's body, as well as the variability in therapeutic response among patients. Thus, it reduces the risk of accumulation of drugs, making the pharmaceutical preparation is quite suitable for re-appointment for cancer patients suffering from acute pain.

The composition according to the invention should contain from 0.05 up to 20 wt.% fentanyl. More preferably, the compositions contain from 0.05 to 5 wt.% fentanyl and especially from 0.1 to 1 wt.%. The content can also be thought of as the amount of fentanyl in a standard drug dose composition, such as a tablet. In this case, the standard dose should contain from 0.05 to 20 mg, and preferably from 0.1 to 5 mg of fentanyl. When using fentanyl in the form of salts, these percentages and quantities should, accordingly, be counted.

According to one preferred aspect of the invention sublingual composition contains a prescribed mixture of one or more bioadhesive and/or mucoadhesive substances media, covered with fentanyl, or one of its pharmaceutically acceptable salts.

According to the invention, it is preferable to obtain a composition using the method of preparation, which includes quick dissolving composition predestinarianism state covers the surface of larger carrier particles. Such compositions are subjected to rapid disintegration in water, dissipating thus the contents of their microscopic particles medicines.

However, to date, has only been reported that prior art use of prescribed mixture for rapid dissolution of the medicinal product suitable for conventional oral drug therapy, i.e. for solid dosage forms that should be swallowed. When receiving such drugs, the dissolution of the particles of the drug occurs in the stomach, i.e. in an environment where there are a relatively large volume of liquid, which can dissolve the drug particles. From all of the previous literature in this area shows that the study of dissolution prescribed mixtures was performed in a large volume of water, usually 1 L. the Possibility of using prescribed mixes for sublingual administration, when the volume of liquid available as solvent, is limited to a few milliliters, was not considered as a feasible approach. Therefore came as a surprise that this form of the preparation of solid dosage form and route of administration give positive and favorable results.

In this observe is yavlyaetsya on a mass basis, determined directly, for example by dry gel filtration, well-known experts in this field.

According to the invention preferably the agent, reinforcing bioadhesion and/or mucoadhesive optionally be added to the carrier particles. Agent, reinforcing bioadhesion and/or mucoadhesive, effectively promotes the attachment of fentanyl for mucous membrane of the mouth and, in addition, can swell and increase in volume upon contact with water and, thus, to facilitate disintegration of the tablet or carrier particles when wetted with saliva. In addition, the agent, reinforcing bio/mucoadhesive must reside on the surface of the particles of the medium, but perhaps he can be present inside these particles, as described below.

The expression “mucoadhesive ' implies the adhesion to the mucous membranes, covered with mucus, such as membrane in the oral cavity, whereas the expression “bioadhesive” implies adhesion to biological surfaces are more General, including the mucous membranes, which are not covered with mucus. In General, these expressions are duplicated as definitions and can usually be used interchangeably, although the expression “bioadhesive” has a wider meaning. In this description and the formula izaberete is reattaching the General term “bio/mucoadhesive”.

Acceptable carrier particles contain from 0.1 up to 25 wt.% enhancing bio/mucoadhesive connections from the whole composition. In fact discovered that the content below 1 wt.% gives insufficient bio/mucoadhesive effect. The preferred range of the content of the agent, reinforcing bio/mucoadhesive, is from 1 to 15 wt.%.

Preferably the agent, reinforcing bio/mucoadhesive is a polymeric substance is preferably a substance with an average molecular weight of more than 5000 (average weight). The level of hydration of the boundary layer agent to enhance the adhesion of the mucous membrane, is set for the display bio/mucoadhesive forces. Therefore, rather than swell the polymer, the more likely is the initiation bio/mucoadhesive. According to the invention hydration bioadhesive compounds also makes them suitable as enhancers of absorption.

Preferably the particle size of the carrier ranges from 50 to 750 μm, and more preferably from 100 to 600 μm. Although you can use the size of the particles outside a specified area, the practical difficulties are identified on practice in the pharmaceutical preparation of particles having such a size. Used media may contain any substance that has Rhodesia to include agent, enhancing bio/mucoadhesive. A number of such substances known to specialists in this field. As relevant examples include carbohydrates such as sugar, mannitol and lactose, or pharmaceutically acceptable inorganic salts such as sodium chloride or calcium phosphate.

In accordance with one particularly preferred aspect of the invention, the carrier also contains a substance that promotes fragmentation. Under the substance that promotes fragmentation, mean brittle material, which is rapidly disintegrated and decomposed, when the pharmaceutical composition of which it forms, pressed into tablets. If the agent enhancing bio/mucoadhesive also included in the carrier and attached to the surface of the carrier, then the other surface agent, reinforcing bio/mucoadhesive can hydrogenate itself. This effect is especially pronounced when the agent enhancing bio/mucoadhesive, also acts as a disintegrator. Found that mannitol and lactose are particularly suitable as an agent contributing to fragmentation.

Adding in the composition of the pharmaceutically acceptable surfactant is preferred feature of the invention. Povided to more rapid initiation bio/mucoadhesive. Surfactant should be in melkodispersionnoy form and homogeneously mixed with fentanyl. The amount of surfactant should be from 0.5 to 5 wt.% from the composition, preferably from 0.5 to 3 wt.%.

As examples of suitable surfactants include lauryl sulfate, Polysorbate, bile salts, and mixtures thereof.

A variety of polymers known in this field can be used as agents that enhance bio/mucoadhesive. In addition to the polymeric nature, what matters is their ability to swell. On the other hand, it is also important that they are essentially insoluble in water. Factor they swell in volume upon contact with water or saliva should preferably be at least 10, while more preferably a factor of at least 20. Examples of such agents that enhance bio/mucoadhesive include cellulose derivatives, such as hypromellose, (receiver array), hydroxyethylcellulose (NES), hydroxypropylcellulose (LDCs), methylcellulose, metilgidroxiatilzelllozu, carboxymethylcellulose and sodium carboxymethylcellulose (NaCMC); starch derivatives, such as moderately poperechnyy starch; acrylic is a (REO); chitosan (poly-D-glucosamine); natural polymers such as gelatin, alginate sodium, pectin; scleroglucan; xanthan gum; guar gum; poly-co-(metilidinovy ether/maleic anhydride); microcrystalline cellulose (avicelRand crosscarmelose. You can also use combinations of two or more bio/mucoadhesive polymers. As a rule, any physiologically acceptable agent characterized by bio/mucoadhesive properties, can be used successfully for inclusion in the media. Bio/mucoadhesive can be determined in vitro, for example according to G. Sala et al., Proceed. Int. Symp. Contr. Release. Bioact. Mat. 16:420, 1989.

Some suitable commercial sources presents bio/mucoadhesive polymers include the following:

The carbopolRacrylic copolymer - BF Goodrich Chemical Co, Cleveland, 08, USA;

HPMC - Dow Chemical Co., Midland, MI, USA;

NEC (natrosol) - Hercules Inc., Wilmington, DE., USA;

HPC (klucelR) - Dow Chemical Co., Midland, MI, USA;

NaCMC - Hercules Inc. Wilmington, DE., USA;

REO - Aldrich Chemicals, USA;

Alginate sodium - Edward Mandell Co., Inc., Carmel, NY, USA;

Pectin - BF Goodrich Chemical Co., Cleveland, OH, USA;

Ac-Di-SolR(modified cellulose resin with a high swelling properties) - FMC Corp., USA;

Actium - Mero-Rousselot-Satia, Baupte, France;

Satukan - Sanofi BioIndustries, Paris, France;

GaN, enhancing bio/mucoadhesive can change the speed and intensity bio/mucoadhesive. In accordance with one of the preferred aspects of the invention, the preferred substances with high and rapid ability to swell.

In order pharmaceutical composition according to the invention to function properly when adding to her agent, reinforcing bio/mucoadhesive, this agent should be placed on the surface of the particle carrier. Agent, reinforcing bio/mucoadhesive, can be added to the mixture of the particles of the medium in several ways. In a preferred direction inventions fine-grained agent, reinforcing bio/mucoadhesive, mixed together with coarse, medium for a sufficient time to obtain the prescribed mixture, where smaller particles exist as individual primary particles attached to the surfaces of the particles of the medium. Thus, the agent, reinforcing bio/mucoadhesive, is added to the mixture in the same way that an active connection; this method is described in European patent 0324725.

In another aspect of the invention, the agent, reinforcing bio/mucoadhesive, in addition to its peripheral location on the surface of the particles of the medium also may aromatica together with melkodispersionnyy bio/mucoadhesive agent in the fluid, which does not dissolve bio/mucoadhesive agent or does not cause swelling. In this case, the dry component parts are first mixed, and the resulting mixture is then moistened not solvent/not causing swelling liquid, such as absolute alcohol. The resulting mass is crushed, for example, by passing it through a filter (gel filtration). Then it is dried and finely ground. Alternatively, the wet mass can be dried and then ground. According to the invention another method of obtaining particles of the medium is the dissolution of the carrier in the solvent which will not dissolve the agent, reinforcing bio/mucoadhesive, or cause it to swell, and then adding to the solution of the agent, reinforcing bio/mucoadhesive, evaporation of the solvent and granulating balance. Other ways also understandable to experts in this field. No matter which way at the back end get a fraction of granules media of the appropriate size containing the agent, reinforcing bio/mucoadhesive, for example, by passing mixtures of particles through the filter (gel filtration) or a sieve with an appropriate pore size, for example, mesh U. S. from 35 to 170.

Preferably the agent, reinforcing bio/muhathuwaram prescribed mixture, their size is within the lower part of the interval sizes and then falls below 10 microns. When the agent enhancing bio/mucoadhesive include particles of the medium, the size of the particles can be within the upper part of the interval size.

The invention, in particular, aimed at the introduction of fentanyl and its pharmaceutically acceptable salts, such as citrate or malate, which do not dissolve quickly in water. Accordingly, particles of fentanyl or its salts have a maximum particle size of about 24 μm, but preferably approximately not more than 10 μm. Fentanyl is able to attach to the carrier particles by the dry mixing of the ingredients for a sufficiently long period of time. This period of time may vary in accordance with the used mixing equipment. Specialists in this field will not have difficulties in experimental determination of the appropriate time mixing for a given combination of active substances, agent, reinforcing bio/mucoadhesive, and media by using a particular mixing equipment.

Another preferred aspect of the invention includes a cage in the composition according to the isomers of disintegrators include poperechnyy polyvinylpyrrolidone, carboximetilkrahmal, natural starch, microcrystalline cellulose, cellulose resin, and mixtures thereof. The preferred content of the disintegrator is from 1 to 10% of the composition. As you can see, the definition of the cage and agent, reinforcing bio/mucoadhesive, to some extent coincide, and may be preferred that both functions were performed by one and the same substance. However, it is important to note that these two classes of fillers are not equivalent, and there are well-functioning disintegrator, which do not show bio/mucoadhesive properties and Vice versa.

Prescribed mixture, prepared in accordance with this invention, can be included in various types of pharmaceutical preparations intended for sublingual administration. Regardless of the form attached to the drug, it is important that the drug is essentially anhydrous, as its characteristic feature is the strengthening of bio/mucoadhesive is the result of his almost instant hydration when making contact with water or saliva. Premature hydration dramatically reduces enhance the adhesion properties and leads to premature dissolution of the active substance.

Pharmaceutical is prescribed for a mixture with conventional pharmaceutical additives and fillers, used for sublingual drugs. Corresponding methods of manufacture are well known to specialists in this field, see, e.g., Pharmaceutical Dosage Forms: Tablets. Volume 1, 2ndEdition, Lieberman H A et al.; Eds.; Marcel Dekker, New York and Basel, 1989, p.354-356, and the literature cited there. Acceptable additives include additional carriers, preservatives, lubricants, agents, providing the sliding, disintegrators, flavorings and dyes.

Thus, the invention provides a dosage form, simple and cheap to manufacture, which enables a quick release of the active substance and enhances the rapid absorption of fentanyl across the oral mucosa. The use of low-dose fentanyl is intended to support short-term actions, as well as to provide opportunities reassignment patients in need of treatment repeated acute or intermittent pain.

The invention is illustrated in more detail by reference to examples representing preferred direction, however, is not restricted by them.

Example 1. Preparation of rapidly decaying tablets with reinforcing bio/mucoadhesive properties

A batch of 1000 tablets received from the and approximately 170 ml of absolute alcohol. The dried mixture was passed through a metal sieve with a pore size of 1 mm mesh, and the resulting fraction having a particle size of approximately from 250 to 450 μm, was mixed with 500 mg of micronized fentanyl and 1.0 g of fine-grained sodium lauryl (surfactant) for 50 hours the mixture was mixed into to 5.0 g of avicelRPH 101 and 10.0 g of alginate sodium (agent, reinforcing bio/mucoadhesive and disintegrator) within 60 minutes the resulting mixture was extruded into pellets at a pressure seal 200 MPa, each tablet had a weight of 100 mg and contained 0.5 mg of fentanyl.

The dissolution rate thus obtained tablets was investigated according to USP XXIII (method of mixing blade) at two different mixing speeds, 25 and 100 revolutions per minute.

Example 2. Preparation of rapidly decaying tablets with reinforcing bio/mucoadhesive properties

A batch of 1000 tablets were received from the following mix: 91,0 g mannitol (granules with a particle size of from 250 to 450 μm) and 1.0 g of sodium lauryl and 500 mg of micronized fentanyl was mixed in a V-mixer for 24 hours thereafter, 5.0 g of avicelRPH 101 and 2.0 g of Ac-Di-SolR(both were used as a disintegrator and as agent, reinforcing the tion 2 minutes The obtained pellet mass was extruded into pellets at a pressure seal 130 MPa. Each tablet contains 0.5 mg of fentanyl.

The disintegration time was tested using the apparatus described in Ph. Eur. (the latest release).

Found that the disintegration time of less than 15 C.

For comparison also got accepted fast dissolving tablets. Dry mannitol having a particle size of between 250 and 450 microns, dry mixed with micronized fentanyl without any further addition of fillers. The mixing time was 50 hours the resulting mixture was extruded into pellets at a pressure seal 200 MPa, each tablet contains 0.5 mg of fentanyl.

The results of this study showed that according to the invention the prescribed mixture with bio/mucoadhesive properties (example 1) has a dissolution rate that is equal to the speed of the conventional fast dissolving tablet composition. A tablet was dissolved within 2 minutes. in Addition, the rapid disintegration established for the tablets of example 2 were the same or even better than the usual tablet disintegration.

Example 3. Evaluation of suction when the hyoid introduction

The patient suffering from intermittent pain sredstv is the situation of fentanyl in plasma was detected within 240 min after injection (results are presented in the drawing). It is seen that the absorption of fentanyl was rapid, reaching its maximum value after 5 minutes it is Shown that according to the invention sublingual medication ensures rapid absorption of the active agent, even if a very small volume of liquid available for dissolution in the way of introduction.

Example 4. Evaluation of bio/mucoadhesive properties

To assess in vitro bio/mucoadhesive properties of the composition according to this invention used way to determine the reinforcing bio/mucoadhesive properties directly on the final dosage forms (Sala, G. E. et al., Proc. Int. Symp. Contr. Release. Bioact. Mat. 16:420, 1989). The assessment was based on measurements of water flow required to remove the active substance from the membrane of the intestine of the rabbit. Strip the mucosa of the rabbit was placed horizontally in a suitable chamber with temperature controlled at 37C. the Fabric is first washed pre-defined volumes of water using a peristaltic pump. Pre-pressed composition according to example 1 (5-15 mg) were then placed on the fabric and left for 2 min to ensure dissolution. That was followed by the elution of water supplied from the peristaltic naaso is tanovich percentage of remote fentanyl. Subsequent studies were performed using increasing speed lucynova flow. The results are presented in the table; the interest is remote at high speed listed for:

A. Bio/mucoadhesive mixture according to the invention (example 1);

Century Bio/mucoadhesive mixture according to the invention (example 2);

C. Traditional mixture for rapid dissolution, not containing agent, reinforcing bio/mucoadhesive.

In the foregoing description the invention has been described with reference to various examples and preferred directions. However, experts in this field it is clear that the scope of the invention is not limited to these examples and directions and that further modifications and changes without departure from the essence of the invention. Thus, the scope of the invention be limited only by the attached claims.

Claims

1. Pharmaceutical composition for the treatment of acute pain by sublingual administration, containing substantially anhydrous mixture of microparticles of fentanyl or its pharmaceutically acceptable salt, attached to the surface of particles in a carrier agent, Wuxi is La, where the particles of the medium more of these particles exhibited, and these particles of the carrier are substantially water soluble and have an average diameter of less than 750 microns.

2. The composition according to p. 1, characterized in that it contains from 0.05 to 20 wt.% fentanyl.

3. Composition under item 1 or 2, characterized in that it contains from 0.05 to 5 wt.% fentanyl, preferably from 0.1 to 1 wt.%.

4. Composition according to any one of paragraphs.1-3, characterized in that the particles of fentanyl have, on a mass basis, the average diameter less than 10 microns.

5. Composition according to any one of paragraphs.1-4, characterized in that the average particle diameter of the carrier after gelfiltration ranges from 100 to 600 microns.

6. Composition according to any one of paragraphs.1-5, characterized in that the medium contains fragile material, which is easily fragmented during pressing.

7. The composition according to p. 1, wherein the carrier particles contain from 0.1 to 25 wt.% agent, reinforcing bio/mucoadhesive, preferably from 1 to 15 wt.% from the whole composition.

8. The composition according to p. 7, wherein the agent enhances bio/mucoadhesive selected from the group consisting of acrylic polymers, cellulose derivatives, natural polymers having mucoadhesive properties and mixtures thereof.

9. The composition according to p. 8, Otley is Lucaya a hypromellose, hydroxyethyl cellulose, hydroxypropylcellulose, sodium carboxymethyl cellulose, methylcellulose, metilgidroxiatilzelllozu, carboxymethylcellulose, microcrystalline cellulose and modified cellulose resin, crosscarmellose, modified starch, acrylic polymers, including carbomer and its derivatives, polyethylene oxide, chitosan, gelatin, alginate sodium, pectin, scleroglucan, xanthan gum, guar gum, poly-co-(metilidinovy ether-maleic anhydride) and mixtures thereof.

10. Composition according to any one of paragraphs.1-9, characterized in that further comprises a pharmaceutically acceptable surfactant in melkodispersionnoy form, homogeneously mixed with fentanyl.

11. The composition according to p. 10, wherein the surfactant is present in an amount of from 0.5 to 5 wt.% from the composition, preferably from 0.5 to 3 wt.%.

12. The composition according to p. 10 or 11, characterized in that the surfactant is selected from the group consisting of lauryl sodium, Polysorbate, bile salts and mixtures thereof.

13. Composition according to any one of paragraphs.1-12, wherein the carrier particles contain a water-soluble, pharmaceutically acceptable carbohydrate and/or reorgani is related substances: mannitol, lactose, calcium phosphate and sugar.

15. Composition according to any one of paragraphs.1-14, characterized in that the carrier particles contain at least one pharmaceutical disintegrity agent conducive to the spread of microparticles exhibited by the sublingual mucosa.

16. The composition according to p. 15, characterized in that disintegrity agent selected from the group consisting of cross linked polyvinylpyrrolidone, carboxymethyl amylum, natural starch, microcrystalline cellulose, cellulose resins, and mixtures thereof.

17. Composition under item 15 or 16, characterized in that disintegrity agent is present in an amount of from 1 to 10 wt.% from the composition.

18. A method of treating acute pain in which the individual is suffering from acute pain, administered under the tongue, at least one standard dose of substantially anhydrous pharmaceutical compositions containing an effective amount of fentanyl or its pharmaceutically acceptable salt in the form of microparticles attached to the surface of particles in a carrier agent, reinforcing bioadhesion and/or mucoadhesive, for the most part attached to the surface of these particles of the carrier, and the average particle diameter of fentanyl, on a mass basis, less than 10 microns, and in which the Method according to p. 18, wherein the fentanyl is introduced in an amount of from 0.05 to 20 mg, preferably from 0.1 to 5 mg standard dose.

 

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