MXPA06009398A - Pharmaceutical composition for oral application and method for preparing thereof - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for oral application comprising:i) an anthelmintic agent;ii) a first excipient having a porous structure with an inner surface of about 500 to 1500 m2/g and a surface area according to BET of up to about 5000 m2/g;as well as to a method of preparing such a composition.

Description

PHARMACEUTICAL COMPOSITION FOR ORAL APPLICATION AND METHOD OF PREPARATION OF THE ORAL BACKGROUND OF THE INVENTION FIELD OF THE INVENTION The invention relates to a pharmaceutical composition for oral application and to a method of preparing it.

DESCRIPTION OF THE RELATED ART Pharmaceutical drugs often have certain desirable properties but an undesirable odor and / or taste. These properties have a great impact on the compliance of the patient and the marketing of the pharmaceutical product. This is especially true for animals having a sense of taste or smell developed extremely well. In general, drug delivery systems for taste masking can be achieved either by chemical or physical modification of a drug powder. The last option is more interesting since the toxicological investigations of the new compound can be avoided. In general, the technologies for masking the physical taste are based on the prevention of interaction between the drug molecule and the oral mucosal surface and several approaches and various manufacturing processes to mask the unpleasant taste of drugs as solid dosage forms have been proposed. .

These include barrier methods (incrustation, coating, encapsulation), the use of flavors and sweeteners and proposals for absorption and composition. In this way the masked-flavored powders are formed by methods known in the art such as spray drying, granulation and coacervation. A review is given, for example, in SUN et al. , (American Pharmeceutical Review, 16-28, 1 999). For composition, absorption and inclusion of bad taste drugs, ion exchange resins, ionic polymers (acrylic acid- / cellulose derivatives, chitosan), cyclodextrins and other additives such as phospholipids or tannic acid have been used. The taste masking of ionic drugs can be achieved by using materials containing basic or acidic groups that interact with the ionisable molecule in this way creating insoluble salts. Since the bitter drugs in an undissolved state have no taste the idea is that the drug is not dissolved, that is, released, during the passage through the mouth. The nature and degree of interaction between the drug and the additive depends on factors such as pK of the drug and the additive, ionic strength, pH of the fluid, solubility of the drug and the chemical structure of the additive. In this way, Prabhu, N. (Indian Journal of Pharmaceutical Sciences), May-June 2002) describes the taste masking of clarithomycin by the tannic acid composition; U.S. Pat. UU No. 5,219,563 (Douglas, S.J., 1990) and U.S. Pat. UU No. 3, 594,470 (Borodkin.S. And Sundberg, D. P., 1971) provide methods for masking taste by charging the anionic drug in a methacrylic acid / divinylbenzene copolymer (Amberlite®). U.S. Pat. UU No. 3,974,272 (Polli, G. P. and Shoop, CE., 1976) provides a method for a cholestyramine coacervate palatable by loading a cationic drug into a styrene / divinylbenzene copolymer (Duolite®). U.S. Pat. U U. No. 5,560,921 (Damani, N.C. and Viehues, R., 1995) and U.S. Pat. UU No.4, 971, 791 (Tsau, J.H. and Damani, N.C., 1990) provide a taste masking method by drug composition with a polymethacrylic polymer. More complicated is the taste masking of neutral drugs by composition / absorption as can be deduced from patent applications with number. Carbohydrates, ex. may contain hydrophobic / lipophilic drugs. More commonly, taste masking is achieved by the inclusion of the bitter drug in cyclodextrin cavities, where the binding of the bitter host molecule within the host cyclodextrin is not fixed or permanent but is in a dynamic equilibrium (Szejtli, J., Medicinal Research Review, 14 (3): 353-386, 1 994). U.S. Pat. No. 5,681, 577 (Lech, S., Schobel, AM and Denick, J., 1995) provides a different approach and method of taste masking by absorption of the drug (pseudoephedrine, dextromethorphan, diphenhydramine) to silicon dioxide, Patent from USA U. U. No. 4,647,459 (Peters, D., Denick, J. and Tawlar, A.K.) uses magnesium trisilicate for absorption. Charcoal is well known and commonly used to prevent absorption of drugs from the gastrointestinal tract in case of poisoning by absorbing them. Charcoal is even used for the purification of blood in hemoperfusion. A less common effect used in medicine is the effect of absorbing charcoal on Escherichia coli or aflatoxin. The indications mentioned above are only dealing with the absorption effect of charcoal. Some researchers, however, have taken into consideration that, as in cyclodextrins, absorption is not a one-way process but there is also something of an opposite effect to the absorption of a charcoal drug. They use charcoal as an excipient to maintain the release of a drug in the gastrointestinal tract (eg Roivas, L et al., Methods Find Exp Clin Pharmacol, 16 (2): 125-32, 1994). However, the sustained release of a drug from an excipient does not automatically lead to the assumption that the excipient can be advantageously used for taste masking of a drug. Hitherto masked taste particles produced by the aforementioned methods often suffer from problems such as: - only drugs that have either cationic functionality (eg salts -COOH or Na / K) or anionic functionality (eg NH2 salts, HCl ) can be used; -the taste barrier is physically damaged during the additional process of the drug to the finished product, eg. by the process of tablet formation; -the barrier is physically damaged during ingestion when chewing. This happens when the particles are too large because only particles smaller than 50 μm (the distance between the taste buds inside the mouth) do not provide a gritty feeling in the mouth. This demand is challenging because small particles have a large range of surface area to volume and dissolve faster in the mouth than larger particles; -the maintenance of acceptable sensory attributes can not be achieved while acceptable bioavailability is reached. This is especially problematic in the case of lowly soluble drugs such as those of the BCS class I and IV system. - A possible problem is that the strength of composition is too strong leading to a sustained release of the drug. - Another possible problem is that some pharmaceutical compositions are using the concept that, at the pH in the mouth (approximately 5.9-7.8), the drug remains insoluble. However this is also the pH that can be found in the intestinal tract and where the drug has to be dissolved because absorption takes place; - commonly used coating or composition agents are soluble or in some way permeable in the pH of the saliva. E.g. Eudragit L (methacrylic acid copolymer A) is soluble at pH 5.5. , Eudragit S (methacrylic acid copolymer) is soluble at pH 7; - the threshold concentration for the bitter taste of the drug is very low; - the drug to be covered has an unfavorable crystal shape, eg, in the case of praziquantel a needle; - the technologies involved are sophisticated ie they are used solvents or risky technologies such as nano particle systems, several stages are necessary during production and / or special equipment; In addition, S.T. Hong et al. , Parasitol Res., October 1, 2003; 91 (4): 316-20 further discloses that it is desirable to apply an anthelmintic drug in a sustained release form when using hydroxypropylmethylcellulose as a carrier. Not only because plasma concentrations are shorter due to its rapid absorption and secretion after ingestion, but also because some of them are mainly acting by direct contact with the parasite in the gastrointestinal tract making it desirable for the dose to remain in the tract gastrointestinal for much longer. Since starch and cellulose are soluble and well-swallowed, respectively, in water, that is to say in saliva, the taste masking of the drug is not entirely sufficient.

BRIEF DESCRIPTION OF THE INVENTION Therefore, it is an object of the present invention to overcome the drawbacks of the prior art, especially to provide a pharmaceutical composition comprising a peptide agent, wherein the pharmaceutical composition exhibits improved taste masking and release. maintained. It is another object of the present invention to provide a method for the preparation of such a pharmaceutical composition. The object is achieved by a pharmaceutical composition for oral application comprising a foreliminary agent and a first excipient having a porous structure with an inner surface of about 500 to about 1,500 m / g and a surface area according to BET of up to about 5,000 Preferably, the agent is a non-charged agent. Still preferably, the agent is selected from the group consisting of macrolides, benzimidazoles, isoquinilones, pyrantel or mixtures thereof. More preferably, the agent is ivermection, febantel, febendazole, praziquantel, epsiprantel or mixtures thereof. More preferably, the agent is praziquantel or epsiprantel. In one embodiment, the excipient is charcoal.

More preferably, the invention is characterized in that the excipient is activated charcoal. An additional embodiment is characterized in that the charcoal has a surface area according to BET of about 1400 to about 2100 m2 / g, preferably about 1700 m2 / g. Preferably, the excipient is present in the composition in an amount of from about 30 to about 98% by weight, more preferably about 50 to about 90% by weight and more preferably to about 70% by weight. Preferably, the excipient having the absorbed agent has a particle size of less than 50 μm. An additional embodiment is characterized in that the agent is preferably absorbed in the internal pores of the excipient. Preferably, the excipient is muco-adhesive in the gastrointestinal tract and / or taste masking. Preferably, the composition comprises a second excipient being absorbed into the core of the first excipient. In a preferred embodiment, the pharmaceutical composition is covered or encapsulated. Preferably, the pharmaceutical composition further comprises adjuvants, flavors, diluents or the like. A further object of the invention is achieved by a method of preparing a pharmaceutical composition according to the invention, comprising the step of mixing the agent and excipient in a dry state. A preferred embodiment is characterized in that the mixing is carried out under high speed agitation. Finally, it is preferred that in a preceding step a second excipient is first absorbed into the core of the first excipient. Surprisingly it was found that with the present invention a masked, preferably muco-adhesive, pharmaceutical composition of small particle size is provided for sustained release independent of additional pH of the active ingredient in the gastrointestinal tract and its method of preparation using a method very simple, free of solvents. By the described procedure, the intimate anterior agent is absorbed to the inner surface of an excipient having a porous structure with a particular surface area providing an effective taste and odor masking effect as well as the sustained release profile. This excipient is preferably activated charcoal. The resulting powder of masked taste can be coated and / or further processed with flavors and other pharmaceutical excipients to form a convenient product. Surprisingly, it was found by the applicant that for the absorption of a hydrophobic / lipophilic compound not only a large surface area of a suitable absorbent particle (excipient) is of greater importance, but especially a specific porous structure. Especially the taste masking is clearly improved when the bitter drug is not absorbed on the outer surface of the excipient but is trapped in the pores. Using charcoal as an excipient, the non-absorption of the anthelmintic agent is detectable in the mouth. The term "excipient having a porous structure" shall mean a porous powder with a larger inner surface capable of absorbing compounds to this surface. In this way the excipient is a highly porous substance providing surface strength to the agent. Result of the interaction of the surface is the accumulation of the agent in the surface region of the excipient. As carriers (absorbent) excipients can be used having pores of nature such as vegetable charcoal (inner surface approximately 500-1500 m2 / g, BET up to 5000 m2 / g) or excipients where the pores are introduced into the particles by special treatment such such as starch (eg, the special quality of potato starch / Nichiden Chemical) or silicates (eg, silica gel). Activated charcoal is therefore most preferred in the current application. In this regard, NORIT A SUPRA® is a preferred activated charcoal having a BET surface area of from about 1700 to about 2100 m2 / g with a methylene blue absorption of from about 35 to about 45 g / 100g of charcoal and a Phenazone absorption of about 45 to about 55 g / 100g of charcoal. Until now, charcoal has not been considered as possessing taste masking properties in pharmaceutical drugs. Surprisingly it was found by the applicant that the incrustation of an unloaded active ingredient, mainly an intimate antelimm agent, within the charcoal the taste of the agent can be extremely masked efficiently. This mainly caused by the fact that the agent is absorbed inside the inner surface (pores). The excipient for the inventive pharmaceutical composition has many muco-adhesive properties allowing the agent to remain in the gastrointestinal tract for a prolonged period of time and providing a sustained absorption of the active ingredient. Such excipient can therefore be used to prolong the systematic absorption of anthelmintic drugs and / or make it available at the local site of action, the intestinal surface. The pharmaceutical composition of the invention can be prepared in a fast and cost effective manner. Preferably, the hydrophobic / lipophilic agent is absorbed into the core or a core mixture of excipient (s). That is, either the agent is directly absorbed into the core or, in a preceding step, another excipient is first absorbed into the core to close the finer pores in this way by improving the release of the agent. A suitable excipient for the preceding step is one of small particle size such as colloidal silicon dioxide. The absorption method is a high-speed mixing of agent and excipient in the dry state or dispersion of the mixture in water or a solvent in which the agent is dissolved. The. Last methods are followed by the evaporation of the solvent. Especially preferred, however, is liquefying by mechanical impact of the agent mixture (hybridization) by the simple, rapid process and dispensing with any additional additive such as binder or solvent. The hybridization technique has been mainly developed by the Japanese company NARA (NARA Machinery Co. Ltd., Tokyo) and is described in EP 0 224 659 A2"Method of improving quality of surface of solid particles and apparatus thereof". Briefly, a dust mixture from the dust inlet is carried on a stream of air generated by the blades rotating at high speed, and circulates in the machine through a circulation tube. Inside the machine, the excipient collides with the agent, the blade, and the interior surface of the machine. By this method the active ingredient is converted directly, by a one-step procedure, in a very uniform product composed of particles of not more than 50 μm. If necessary, the kinetics of dissolution of the pharmaceutical composition thus processed can be modified by conventional coating or embedding methods.

DETAILED DESCRIPTION OF THE INVENTION The invention is now illustrated by way of example with reference to the accompanying drawings, wherein the figure shows the dependence of dissolution in time for a praziquantel powder of sustained release and masked taste. The present invention is illustrated using the active ingredient prazinquantel, a hydrophobic / lipophilic anthelmintic drug with short half-time elimination having a low solubility in water and being extremely bitter in flavor. A pharmaceutical composition of the invention can be preferably used in the treatment of animals with a foreling agent. A good flavor masker and sustained release of praziquantel was achieved by the following mixture: The corresponding amount of charcoal and Aerosil are mixed (40-300g) and introduced into a NARA Hybridization System, NHS Type 1. The mixture is processed for 3 minutes at 6000 rpm. To this premix the praziquantel ingredient was added and the final mixture was again processed for 3 minutes at 6000 rpm. Several factors can influence dissolution profiles of drug release systems such as pH, thickness and type of coating or surface wettability. In the case of praziquantel the delay in drug release needs to be long enough to pass the oral cavity, followed by a convenient release (fast or maintained) in the gastrointestinal tract. Praziquantel has a very low solubility in water and the dissolution according to USP has to be "not less than 75% after 60 minutes". Under conditions such as those described in USP for praziquantel tablets the release of praziquantel from the powder according to the invention is approximately 50% after 10 minutes it continues for a slow release reaching approximately 65% after 80 minutes (see figure below). It is surprising that the release at the site of action is rapid although the taste of the absorption complex remains perfect in the mouth. It should be emphasized that the threshold concentration for bitter taste of praziquantel is very low. The release in the gastrointestinal tract is adapted to the indication due to the presence of worms in the stomach, not only in the intestine; moreover, although hitherto not performed in dosage forms a prolonged release of praziquantel is desirable (eg as recently explained by Hong S.T., supra). It can be concluded that the pharmaceutical composition for oral application of this invention is different from conventional formulations for taste masking and / or mucoadhesive action due to the excipients used and the extreme ease and speed of its production. Additional advantages are that the dissolution of the unflavored complex is not pH dependent, that its particle size is within the range of micronized powders, that there is no artificial odor of excipients as in polymers such as methacrylates (especially useful in medicine veterinary) and that the taste barrier can not be physically damaged during a tabletting process. The features disclosed in the foregoing description, the claims and / or the accompanying drawings may, separately and in any combination thereof, be material for the embodiment of the invention in various forms thereof.

Claims (18)

1. CLAIMS 1. Pharmaceutical composition for oral application comprising: i) an anthelmintic agent ii) a first excipient having a porous structure with an inner surface of about 500 to about 1,500 m2 / g and a surface area according to BET of up to about 5,000 m2 / g.
2. 2. Pharmaceutical composition according to claim 1, wherein the agent is a non-loaded agent.
3. 3. Pharmaceutical composition according to claim 1 or 2, wherein the agent is selected from the group consisting of macrolides, benzimidazoles, isoquinolones, pyrantel or mixtures thereof.
4. 4. Pharmaceutical composition according to claim 3, wherein the agent is ivermection, febantel, fenbendazole, praziquantel, epsiprantel or mixtures thereof.
5. 5. Pharmaceutical composition according to any of the preceding claims, wherein the excipient is charcoal.
6. 6. Pharmaceutical composition according to claim 5, wherein the excipient is activated charcoal.
7. 7. Pharmaceutical composition according to claim 6, wherein the charcoal has a surface area according to BET of about 1400 to about 2100 m2 / g, preferably about 1700 m2 / g.
8. 8. Pharmaceutical composition according to any of the preceding claims, wherein the excipient is present in the composition in an amount of from about 30 to about 98% by weight, more preferably about 50 to about 90% by weight and more preferably to about 70% by weight.
9. 9. Pharmaceutical composition according to any of the preceding claims, wherein the excipient having the absorbed agent has a particle size of less than 50μm.
10. 10. Pharmaceutical composition according to any of the preceding claims, wherein the agent is preferably absorbed by the interior pores of the excipient. eleven .
11. Pharmaceutical composition according to any of the preceding claims, wherein the excipient is mucoadhesive in the gastrointestinal tract.
12. 12. Pharmaceutical composition according to any of the preceding claims, wherein the excipient is taste masking.
13. 13. Pharmaceutical composition according to any of the preceding claims, wherein the composition comprises a second excipient adsorbed to the core of the first excipient.
14. 14. Pharmaceutical composition according to any of the preceding claims, wherein the pharmaceutical composition is covered or encapsulated.
15. 15. Pharmaceutical composition according to any of the preceding claims, wherein the pharmaceutical composition further comprises adjuvants, flavors, diluents or the like.
16. 16. Method of preparing a pharmaceutical composition according to any of the preceding claims, comprising the step of mixing the agent and the excipient in a dry state.
17. 17. Method according to claim 16, wherein the mixing is carried out under agitation with high speed. The method according to claim 16 or 17, wherein in a preceding step a second excipient is first absorbed in the core of the first excipient.