Quick-breaking chitosan-based granules

FIELD: pharmaceutical industry.

SUBSTANCE: invention relates to porous quick-breaking active ingredient-containing granules based on chitosan or basic derivative thereof prepared by drop-by-drop technique, wherein aqueous solution or dispersion of chitosan or basic derivative thereof, one or several active substances, optional secondary active substances, and acid are dropwise added to cooling fluid at maximum temperature -5°C. As a result, solution or dispersion is solidified in the form of drops, which are then separated and dried. Such procedure is used to prepare therapeutical or diagnostic agents.

EFFECT: avoided use of gelatin or collagen as carrier.

16 cl

 

The invention relates to the production of rapidly disintegrating carriers of the active substance in the form of particles. In particular, the invention relates to a method of manufacturing a porous containing the active substance granules for oral administration of chitosan-based or primary derivative of chitosan. In addition, the invention relates to granules based on chitosan obtained in this way and their use for the manufacture of drugs and diagnostic agents.

Carriers of the active substance in the form of particles distributed widely in the pharmaceutical industry. They have less weight and are more compact in comparison with other means of oral administration, such as liquid dosage forms, as well as have a higher chemical stability and allow more precise. Advantage of drugs on the basis of a set of particles, such as granules, on drugs in “single form”, such as the pill, is higher reproducibility of their behavior, especially in the case of exposure to physiological factors, subject to significant changes. This is because when you receive a large number of granules in their behavior as a whole develops according to the statistical models within the middle of the mathematical expectation and the influence of individual sharply distinguished values are not so great, as in the case of tablets.

There are a large number of media materials used in the manufacture of pellets. Usually they are biocompatible substances with different chemical, physical-chemical and mechanical properties. In particular, their choice depends on the technical, economic and regulatory factors, such as compatibility of the material of the carrier with the active ingredient (s), the ability to disintegrate and dissolve, stability of the drug, raw material cost, machinability, permission of the regulatory authority for oral administration, etc.

In addition to the pellets used in the drugs controlled release of the active substance, also known rapidly disintegrating granules, able to quickly release the contained active ingredient. Appropriate dosage forms based on them, also known as potent form, are particularly preferred in the case of sporadically occurring indications for which the drugs act should occur as soon as possible. Their examples are analgesic, antitussive, anti-allergic, anti-asthmatic, protivoalergicescoe and other means. The substance of the media in such preparations is usually hydrophilic or water soluble, due to CEG which will ensure the required ability to disintegrate. However, this ability also depends on such additional factors as the presence of so-called agents, causing disintegration, i.e. substances that can absorb water and greatly to swell, or as much as possible effective surface.

Granules with a larger outer surface are small. In order to ensure the effective decomposition of the surface should be wetted, which is ensured by selection of the material of the carrier or adding wetting agents. Alternatively, the surface may be increased due to high porosity. In this case, the diameter of the particles plays only a minor role.

In the Federal Republic of Germany patent 4201172 C1 described granules, as active ingredient containing aloe Vera extract, and as a carrier of gelatin or collagen, and the collagen is preferably soluble in cold water.

As the carrier can also be used for additional substances such as dextran, sugar, alcohol, glycine or polyvinylpyrrolidone. To obtain can be used as drip method, for example, by using the device disclosed in the patent Germany 3711169 A1, in which the granules are obtained by hardening the droplets in the coolant, preferably liquid nitrogen. In the subsequent freeze-drying receive the desired end product is t, high porosity and rate of decomposition.

In the Federal Republic of Germany patent 4201173 A1 also discloses such granules, which, however, contain a derivative of dihydropyridines as the active substance.

Upon receipt of such grignano on the basis of gelatin used long known the applicability of the material of the carrier for the freeze drying process for the manufacture of porous products. In particular, in Germany sell this kind of products for oral (e.g., Imodium®, obtained by freeze-drying lingual tablets or the leafs company Janssen-Cilag) and parenteral (for example, dry Mumpsvax®) applications.

The drawback of such preparations containing gelatin or collagen, is the fact that their efficiency is adversely affected by concerns of patients associated with the risk of BSE infection. In this regard, many patients and doctors prefer not containing gelatin preparations.

Thus, the present invention is to provide a method of manufacturing a porous rapidly disintegrating granules without the use of gelatin, collagen or derivatives thereof. An additional object of the invention is the creation of not containing gelatin and collagen porous rapidly disintegrating granules serving as a carrier of the active substance in the manufacture of medicinal and diagnostic medium spans the century

This goal is achieved by the present invention by a method according to claim 1.

It was found that using the drip method, which as the carrier of the active substance used aqueous dispersion of chitosan or a primary derivative of chitosan, and complied with other provisions under item 1, it is possible to obtain cryogeny or granules, freeze-dried method, the quality of which is comparable with the quality known from the technology of granules containing gelatin.

The granules according to the present invention are solid particles of spherical or nearly spherical shape with a diameter of from about 0.1 to 6 mm Single dose of a pharmaceutical product on the basis of granules consists of numerous granules, which quickly disintegrate, i.e. granules are not delayed, deferred, adjustable or variable release of the active substance. Despite the fact that the rate of release of the active substance may not be equal to the decay rate of the pellets, however, these two processes are interrelated, and therefore quickly disintegrating preparations used in cases where the purpose of creating potent dosage forms is required as the rapid release of the active substance, and rapid onset of its action. Typically, these drugs are broken down into physical and the ideological liquids within a few minutes. In addition, the granules are porous, i.e. have an internal surface area of which is comparable with the size of their outer surface.

A method of manufacturing granules according to the present invention is characterized by the presence of a sequence of stages, including if necessary, the specialists in the art may include additional stages, carried out before, between or after the stages described method.

At the first stage of implementation of the method are water rasters or dispersion, in which the chitosan or a derivative of chitosan, one or more active substances, auxiliary substances and acid are predominantly in the dissolved form, i.e. undissolved portion is substantially less than the dissolved part. In particular, this applies to the chitosan or the principal derivative of chitosan used as a carrier of the active substance pellets. However, in the case of chitosan in the form of suspension of the granules will not have sufficient cohesion.

Like most biopolymers, chitosan, which itself is a derivative, in particular a product of the partial deacetylation of a natural polymer chitin, various ways can be obtained derivatives with a modified chemical and physico-chemical properties. the main derivative of chitosan is a polymer, derived from chitosan by modifying its chemical, biological or physical properties, however, like the chitosan has a positive charge. As a result of these changes the number of positive charges may be less than the original polymer. For this reason, in the molecule of the derivative can be negative charges. To achieve the objective of the present invention can be applied to any biocompatible derivative of chitosan, provided that it generally has a positive charge or the number of its positive charges exceeds the number of negative charges. Preferred are derivatives of chitosan obtained by acetylation.

Among the preferred species is not modified chitosan comprises a chitosan with a molecular weight above 40,000 units, and particularly preferred are the chitosans with molecular weight of more than 75,000 units. In the preferred embodiment is not subjected to a change of chitosan, the degree of acetylation ranging from 10 to 50%, and especially preferred chitosans with a degree of acetylation of from 20 to 45%.

The advantage of chitosan or its derivatives is that these biopolymers have a particularly high biological tolerance and are easy to get from chitin, which is the de is the combat and widely available raw materials and eliminating the risk of exposure to BSE.

Although chitosan is mostly insoluble in water, its solubility is noticeable when the change in pH towards acidity. Thus, to provide the desired concentration of polymer required to obtain a solution or dispersion, while using acid. To facilitate subsequent removal of the acid from the pellets, it was found that the acid should have a low boiling point, and it is preferably not higher than 140°S, more preferably not higher than 130°S, even more preferably not higher than 100°S, particularly preferably not higher than 80°as, for example, hydrogen chloride, hydrogen bromide, triperoxonane acid, formic acid and acetic acid. Can also be used acid, forming a low-boiling binary azeotrope mixture with water, such as acetic or propionic acid. Preferably it is biocompatible acid, however, it is possible to apply the acid with a lower tolerance, subject to its complete removal later from granules. This condition is more difficult to perform in relation to acids, boiling point which is close to the boiling point of water or exceeds it, because it requires a more intensive mode of drying, can lead to the dryness of the product and decomposition of the active substance. Ethypicone sensitive to drying dried under reduced pressure or by sublimation.

In the most General sense, the active substance is a substance used to provide pharmacological effects in humans or animals or on an organism. In addition, this term includes substances used for diagnostic purposes.

In the solution or dispersion may optionally be present pharmaceutical auxiliary substances known to specialists in this field of technology. One of them may, in particular, to enter additional polymer or polimernye substances media, as well as stabilizers, surfactants, activators decay, antioxidants, dyes, pigments, flavors, sweeteners or other improves the taste of substances, binders, etc.

At a subsequent stage of the method the aqueous solution or dispersion dropwise served in the coolant temperature does not exceed -5°where it solidifies in the form of separate drops. Such drops can be obtained, in particular, with the device type pipette, needle or nozzle through which is fed under pressure an aqueous solution or dispersion. With the falling of drops usually are via air or protective gas phase and acquires a spherical shape, which they retain after their immersion in the coolant, where they harden in the IDA drops, globe-shaped or close to it. Varying the number of well-known experts in the field of engineering parameters, such as density and specific viscosity of the aqueous phase, shape, diameter, interfacial tension device drip feed and so on, you can get droplets of varying size. In preferred variants of the invention, the droplets have a size of from 0.3 to 5 mm, the droplet Size influences the size of the granules obtained according to the proposed method, despite the fact that these two values should not be compared to each other. As a rule, the most probable droplet size is slightly larger than the most probable size of the granules.

For immediate solidification temperature of the coolant need to be maintained below 0°and to complete the task of the invention is not higher than -5°C. is Preferred variant of the invention, in which a coolant temperature below -15°C. Particularly preferred are coolants, representing obtained by the method of freeze-drying inert liquefied gases or gas mixtures, such as liquid air or liquid nitrogen. Such an implementation option most likely to deliver immediate solidification of an aqueous solution or dispersion after its immersion ohlazhdaemoy liquid. In addition, coolers of this kind is very simple and can almost completely be removed from the product.

For additional stages of the method of the hardened drops, now representing granules, separated from each other. This operation is carried out in various ways depending on the device configuration drip feed and cooling unit. One of the easiest ways is to supply coolant containing granules through a coarse filter, during which there is simultaneous sorting granules in size. The granules according to the invention, obtained as described, have a size of from about 0.3 to 5 mm, Preferably a diameter of the granules is from 0.8 to 3 mm

Additional progress way separated in this way, the granules are dried. Given the high water content temperature in the separation and drying of the granules at normal pressure should not exceed approximately 0°C. However, it is recommended is preferred according to the present invention to carry out the freeze-drying under reduced pressure, thereby removing water from the granules also improves at higher temperatures by sublimation, thereby gain granules with a highly porous structure. The relevant settings and parameters PR is the process known to specialists in this field of technology.

In addition to the open method of manufacturing the invention also relates to the granules obtained in this way. In accordance with the foregoing, these granules are spherical porous rapidly decaying particles with a preferred diameter of from 0.3 to 5 mm, particularly preferred from 0.8 to 3 mm in Addition. their composition is chosen so that, according to a preferred variant implementation they have a surface charge components in terms of Zeta-potential ranging from +0.5 to +50 mV. The presence of such a surface charge is due to the fact that the substance of the carrier granules is mainly chitosan or a derivative of chitosan.

To facilitate handling of the granules and simplify their application granules can be produced in the form of doses of prisoners in hard capsules made of gelatin or similar hard capsules from starch or other polymers.

Despite widespread use for this purpose hard capsules made of gelatin, taking into account the above-mentioned problems BSE, more may be preferred, other material for capsules, for example starch, does not impact the actual capsules.

Alternatively, the reception in the form of hard capsules can also be taken in the form of a soluble drug. In this case, the granules is in the tank containing multiple doses, Lieb is in the form of doses, Packed in small bags, placed in water or other liquid in which they disintegrate, forming a ready-to-eat product in the form of a drink. In the case of such applications, but also in the case of hard capsules, granules according to the present invention must be mixed with auxiliary substances, affecting, for example, fluidity, adhesion ability, stability, etc. of the granules. With the aim of obtaining drugs or diagnostic tools granules according to the present invention may be subjected to any additional processing.

1. A method of making droplets porous, rapidly decaying, containing the active substance pellets chitosan-based or primary derivative of chitosan, wherein (a) obtain an aqueous solution or dispersion, in which the chitosan or a derivative of chitosan, one or more active substances, acid with a boiling point of not higher than 140°With possible additional excipients mainly present in the form of a solution, (b) an aqueous solution or dispersion dropwise served in the coolant with a maximum temperature of -5°, where it solidifies in the form of droplets; c) solidified droplets or granules separated and d) is dried and the acid is removed from the granules.

2. Methods for the manufacture of porous, rapidly disintegrating containing the active substance granules according to claim 1, characterized in that the drying of the separated granules carried out by sublimation.

3. Method of making porous, rapidly decaying, containing the active ingredient granules according to claim 1, characterized in that the coolant temperature is less than -15°C.

4. Method of making porous, rapidly decaying, containing the active ingredient granules according to claim 1, characterized in that the cooling liquid is a liquefied gas or sizenew gas mixture.

5. Method of making porous, rapidly decaying, containing the active ingredient granules according to claim 1, characterized in that the coolant is a liquid air or liquid nitrogen.

6. Method of making porous, rapidly decaying, containing the active ingredient granules according to claim 1, characterized in that the diameter of the droplets ranges from 0.3 to 5 mm

7. Method of making porous, rapidly decaying, containing the active ingredient granules according to claim 1, characterized in that the molar mass of chitosan or a derivative of chitosan is more than 40 000.

8. Method of making porous, rapidly decaying, containing the active ingredient granules according to claim 1, characterized in that the molar mass of chitosan or a derivative of chitosan exceeds 75 000.

9. The method of producing the texts porous, rapidly disintegrating containing the active substance granules according to claim 1, characterized in that the degree of acetylation of chitosan or a derivative of chitosan ranges from 10 to 50%.

10. Method of making porous, rapidly decaying, containing the active ingredient granules according to claim 1, characterized in that the degree of acetylation of chitosan or a derivative of chitosan ranges from 20 to 45%.

11. Method of making porous, rapidly decaying, containing the active ingredient granules according to claim 1, characterized in that the main derivative of chitosan is an acylated chitosan.

12. Porous, rapidly decaying, containing the active substance pellets chitosan-based or mainly derived chitosan, characterized in that these granules are manufactured by the method according to claim 1.

13. Porous, rapidly decaying, containing the active ingredient granules according to item 12, characterized in that the Zeta-potential is in the range from +0.5 to +50 mV.

14. Porous, rapidly decaying, containing the active ingredient granules according to item 12, wherein the average diameter of from 0.3 to 5 mm

15. Porous, rapidly decaying, containing the active ingredient granules according to item 12, wherein the average diameter of from 0.8 to 3 mm

16. Porous, rapidly decaying containing acting the substance granules indicated in paragraph 12, characterized in that the granules are in a hard capsule.



 

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