Tablet with intersolubility coating and method of preparation

 

(57) Abstract:

The invention relates to medicine and relates to tablets with intersolubility coating and method of its preparation. The tablet contains the drug, are sensitive to low values of pH below 3, such as 2', 3'-dideoxyinosine, intersolubility coating derived from a methacrylic acid copolymer and plasticizer. Tablets may be of different size and may be taken orally individually or many tablets, sufficient for a given dose can be encapsulated in a soluble capsule. Tablets have excellent resistance to degradation at pH below 3 and excellent properties for selection of medicinal substance with a pH higher than 4.5. 2 C. and 38 C.p. f-crystals, 4 PL.

The invention relates to pharmaceutical compositions in the form of tablets with intersolubility coating that contains unstable in the acid product with a high drug load, such as ddI, sensitive to the environment with a pH of less than 3, and which includes intersolubility floor, such as Eudragit L-30-D55 and a plasticizer, which does not require sublayer (supporitve). Tablets have excellent resistance to degradation at pH less than 3, what about making the specified composition.

Intersolubility coverage for many years was used to prevent the release of drug substances from the oral input of dosage forms. Depending on the composition and/or viscosity intersolubility coating resistant to gastric acid, within a reasonable period of time before they start to deteriorate, making it possible slow allocation of medicinal substance in the lower part of the stomach or in the upper part of the small intestine. Examples of some intersolubility coatings are given in U.S. Patent 5225202, such as beeswax and glycerylmonostearate; beeswax, shellac and cellulose; and cetyl alcohol, resin mastic tree and shellac and shellac and stearic acid (U.S. Patent 2809918); polyvinyl acetate and ethylcellulose (U.S. Patent 3835221); and a neutral copolymer of esters of poly (methacrylic acid (Eudragit L30D) (F. W. Goodhart et al., Pharm. Tech., pp. 64-71, April 1984); copolymers of esters of methacrylic acid and methyl ester of methacrylic acid (Eudragit, Eudragits), or a neutral copolymer of esters of polymethacrylic acid containing metallic stearates (Mehta et al., U.S. patents 4728512 and 4794001).

Most intersolubility polymer starts to become soluble at pH 5.5 and above, PR is ski composition, covered intersolubility shells and/or prolonged action, and methods of preparing these compositions described in the art. The composition of the previous prior art, however, often, in addition to medicinal substances, contain a lot of additional ingredients, such as fillers, agents for buffering, binders and lubricants, which are added to increase the volume of the composition and reduce the amount of active drug that can be contained in the composition. The preparation processes of these above-mentioned pharmaceutical compositions require many long stages, including the stage of application sublayer (supporitve) and external coatings. In addition, many of these pharmaceutical compositions are intended for delivery in the lower region of the gastrointestinal tract, i.e. in the rectum, in contrast to the upper part of the intestine, i.e. the duodenum of the small intestine.

In U.S. Patent 5225202 described pharmaceutical compositions with intersolubility coverings using floor of the neutralized polymer phthalate of hydroxypropylmethylcellulose (NRSR). Described pharmaceutical compositions contain a base, disintegrant, EDINOGO coverage, and intersolubility coating and plasticizer. The pharmaceutical composition may also contain one or more fillers, lactose, sugar or starch. According to the invention covered by this reference, when the Foundation - the core - is a medicinal substance is not compatible with the layer Intercollege coverage, then to prevent interaction between unstable in acid drug substance and acidic intersolubility coating used additional sublayer, which behaves as a physical barrier between the core and outer layer intersolubility shell. The process of dissolution intersolubility shell of NRMR begins at pH 5.0. Method of preparation of such pharmaceutical compositions requires a multi-stage coating process to create a sublayer, and then intersolubility shell.

U.S. patent 5026560 encompasses a pharmaceutical composition and method of preparation mentioned pharmaceutical composition, wherein the pharmaceutical composition comprises a core the size of a seed apples "moisturizing miracle" produced by coating of sucrose, corn starch, coating on the core of an aqueous binder in water or ethanol solution and nepalease edusim applying Intercollege coverage.

In U.S. Patent 4524060 described pharmaceutical composition of prolonged action for therapeutic treatment of patients with hypertension, which comprises a mixture of finely ground indoramin or its pharmaceutically acceptable salt of vodokanalavtomatika, wetting agent, agent, causing the disintegration, the mixture is in the form of non-compacted granules and has intersolubility floor of prolonged action, permeable to gastric juice.

U.S. patent 5536507 relates to pharmaceutical compositions with a coating providing a prolonged action, or intersolubility coating, the active agent is in this form that the main quantity of medicinal substance stands near the entrance to the colon or large intestine at pH approximately 6,4-7,0.

Pharmaceutical compositions containing a medicinal substance is unstable in an acidic environment, such as environment in the stomach, and inadequately buffered require Intercollege protective coating to prevent the release of such medicinal substances before getting into the intestine.

ddI (also known as DDI or 2',3'-dideoxyinosine and manufactured by Bristol-M formula

< / BR>
and, as has been shown, is effective for the treatment of patients infected with the HIV virus that causes AIDS. It was reported on the composition and method of inhibiting HIV replication with 2',3'-dideoxyinosine (see U.S. Patent 4861759, 5254539 and 5616566). Recently Videxhas become widely used as a component of new therapeutic cocktails used to treat SPID and. It is also a medicinal substance that is unstable in acidic medium, are sensitive to low pH environment and disintegrating in the stomach.

Videxusually produced in different dosages for prolonged taking, including chewable/dispersible buffered tablets containing didanosine 25, 50, 100 or 150 mg Each tablet buffered with calcium carbonate and magnesium hydroxide. Tablets Videxalso contain aspartame, sorbitol, microcrystalline cellulose, polyplasdone (Polyplasdone), flavouring with Mandarin-orange smell and magnesium stearate. Videx- buffered powder for oral solution is available for oral administration in the form of packets with a single dose containing 100, 167 or 250 mg of didanosine. Each package, along with a dose of the product of the first acid and sucrose. Also issued Videxbaby powder for oral input solution in glass vials with a capacity of 4 or 8 oz (~ 118 ml 236 ml) containing 2 or 4 grams of DDI, respectively, which is necessary before admission (through the mouth) to mix with the sales antacid.

Despite the fact that during therapy focuses on the pill, either taken individually or as part of combination ("cocktail"), modern chewable/dispersible buffered tablets are not very convenient from the point of view of ease of use for patients. While other products, which is part of therapeutic cocktail for SPEED e are capsules or tablets and are easily swallowed, Videx(in this description referred to "ddI") chewable/dispersible buffered tablets should be thoroughly chewed, manually grind or make a homogeneous suspension in water before taking. As ddI rapidly decomposed by acid pH, ddI chewable/dispersible form and in the form of buffered powder for oral solution contains agents for buffering and entered with antacids in the form of baby powder. However, the presence in the formulation of large quantities of antacid components may cause znachitelnoi chew large ddI tablets (dose=2 tablets of 2.1 g each), the taste of the tablets or the time required for dispersion of tablets and liquid (4 oz, 118 ml) per dose. All these facts combined with the fact that manufactured drugs other nucleoside analogues in a more accessible form (e.g. capsule or tablet smaller), require the creation of new lekarstvennoi form of ddI, which is easily GLORIETTA and does not cause unpleasant side effects.

Accordingly, it is proposed a pill that contains the core of the medicinal product and the shell (coating), which prevents the release of the drug in the stomach and makes it possible drug release in the small intestine, which makes unnecessary the use of antacid that with constant use can cause the LCD imbalance. I.e., pharmaceutical compositions containing the medicinal substance is unstable in an acidic environment, such as in the stomach, require a protective coating to prevent the release of such medicinal substances before getting into the intestine.

In accordance with this invention offers covered intersolubility shell heavily loaded pharmaceutical composition and method of obtaining this pharmaceutical composing this prevents intersolubility floor. The pharmaceutical composition according to the invention, mainly in the form of tablets, includes a base containing a medicinal substance, such as ddI, sensitive to the environment with a low pH value, and, if necessary, a binder or a filler, a substance that promotes disintegration, or a substance that promotes swelling and lubrication. In addition, there intersolubility sheath covering the base, which contains methacrylic acid copolymer and a plasticizer.

New pharmaceutical drug with intersolubility coating according to the invention provides protection of drug or therapeutically active agent, such as ddI, at pH below 3 (as in the stomach), but allows the release lekarstvennogo substances at pH 4.5 or higher (as in the upper part of the intestine).

Accordingly, the pharmaceutical composition according to the invention usually contains medicinal substances, chemically unstable in acidic media. The pharmaceutical composition according to the invention provides excellent protection in very acidic environments (pH<3), without impeding the quick release on sites with a pH above 4, regardless of whether it occurs in the upper part of the intestine or duodenum. the and, therefore, upon contact with kislotoneustoichiwami ingredients can cause chemical instability. This is especially true at high temperature and in a humid atmosphere, in which the process water coverage. To minimize this is caused by the acid instability between particles, beads, granules, tablets, etc. and intersolubility coating is usually placed a protective coating or sublayer. This protective coating is physically separates labile in acid lekarstvennoe substance from acid Intercollege coverage and, therefore, improves the stability of the formulation. The process of applying such a sublayer, however, often consists of many tedious and lengthy stages. In addition, the underlayer may slow drug release.

I.e., describes a technique in which the tablets, beads, granules and/or particles containing unstable in acid drug substance, can be successfully cover intersolubility shell in water without the use of a protective layer or sublayer. This method involves raising the pH of the suspension Intercollege flooring using alkalizing agents. The pH value of the suspension pokr is with may also include the introduction of a binder, such as sodium carboxymethyl cellulose, fillers, such as microcrystalline cellulose, substances that promote disintegration, such as alkaline starch, and other excipients such as magnesium oxide, having a relatively alkaline recipes offer Intercollege coating cores. Raising the pH of the slurry coating gives a more stable composition is unstable in acid drug substance in the nucleus. In the result, there is no incompatibility and eliminates the need for protective sublayer between unstable in the acidic environment of the medicinal substance and the acidic intersolubility coating. In this way you are not only additionally increases the cost of stage application sublayer, but also achieves a more rapid drug release, as an additional sublayer slows down the allocation of medicinal substances.

The method according to this invention illustrates the preparation of tablets with high content (99.5% of uncoated tablets) are unstable in the acidic environment of drugs such as ddI, using the water method. You do not need any special equipment, as it was found that for formosana coverage.

In the digestive tract coated tablets first pass through the stomach. The time of passing through jeddak is approximately two hours and the pH at this site is approximately 1-3. Component Intercollege coating allows the kernel with lekarstvennym substance to remain virtually intact and, therefore, prevents the release of pharmacologically active substances on this site or the penetration of the acid in the core tablets. Then the tablet passes through the small intestine, the major part of the component Intercollege coating dissolves and releases the pharmacologically active substance. In the normal direction of flow of the small intestine consists of the duodenum and the ileum. The time of passage through the small intestine is approximately 2-4 hours and the pH at these sites is approximately 5-7,2.

Used in this description, the term "intersolubility coating" means a polymeric material or material(s) which cover(s) kernel-based drug substance. Polymeric material Intercollege coating according to this invention does not contain any active compounds, i.e., any therapeutically active agent, in this coedine were dissolved, before drug or therapeutically active agent released from the dosage form, so as to achieve a prolonged dissolution basics - medicinal substances. Suitable pH-sensitive polymer is one which is soluble in intestinal juices at higher pH values (pH higher than 4.5), such as in the small intestine, and, therefore, allows the release of pharmacologically active substances in the area of the small intestine and not in the upper area of the LCD tract such as the stomach.

The polymeric coating material is chosen so that therapeutically active agent is allocated when the dosage form reaches the small intestine or land on which the pH is higher than 4.5. Preferred pH-sensitive coating materials, which remain intact at lower pH environment in the stomach, but disintegrate or dissolve at pH values normally observed in the small intestine of the patient. Polymeric material Intercollege coating begins to dissolve in an aqueous solution at a pH of about 4.5 to 5.5. The dependence of solubility intersolubility polymers according to this invention is such that an appreciable dissolution of the polymer Intercollege pokr is moved approximately from 4.5 to 6.5 in the bulb of the duodenum to about 7.2 in the distal regions of the small intestine (the ileum). To ensure predictable dissolution corresponding to the time of passage through the small intestine is about 3 hours, and reproducible release them, the coating should start to dissolve in the range of pH in the duodenum and continue to dissolve at pH values in the small intestines. Therefore, the number Intercollege polymer coating should be such that it almost disappeared from sight for about three hours transit time through the small intestine.

Pharmaceutical drug in the core is unstable in acid drug substance, such as ddI, pravastatin, erythromycin, digoxin, Pancreatin, ddA, ddC, etc., This invention is not limited to these medicines, other pharmaceutical substances can also be used. The invention is particularly suitable for pharmaceutical compositions such as tablets, which as a medicinal substances contain ddI. ddI is present in amounts of about to 95% of the composition in the coated tablets.

In the kernel (basis) may contain one or more binders or fillers. Microcrystalline cellulose (PH 101) is preferred due is to use include sodium carboxymethyl cellulose AvicelTMPH101, AvicelTMRC 591, AvicelTMCL-611 (FMC Corp. ), Ceolus (FMC Corp.), ProSolvTM(Edward Mendell Co.), MethocelTME-5 (Dow Corp. ), Starch 1500 (Use Co., Ltd.), the hypromellose (receiver array) (Shin-Etsu Chemical Co., Ltd.), polyvinylpyrrolidone, potassium alginate and sodium alginate.

The core (base) of the composition according to the invention may also include one or more substances that promote disintegration (grinding) or swelling, such as sodium derivative of starch (alkaline starch), available under the trade name EXPLOTAB (Edward Mendell Co.), Ac-Di-Sol (cross-linked sodium carboxymethylcellulose) (FMC Corp.), sodium croscarmellose, corn starch or crosslinked polyvinylpyrrolidone. A lubricant such as magnesium stearate, can also be used in the preparation of uncoated tablets, namely as a lubricant during the extrusion and pelletizing.

The core (base) used in the pharmaceutical composition according to the invention are in the form of tablets, preferably round, biconvex tablets, approximately 3/16 inch (4.76 mm). This invention, however, does not limit the size of the pills and tablets can be prepared in different sizes. Tablets are smaller, however, preferred, as they are easier to pass through the stomach than pills larger p is a state of matter, has the same bioavailability as the granule described in the simultaneously rassmatrivaemoi application U.S. 09/083597, filed may 22, 1998. Depending on the size of the tablets can be swallowed separately, or multiple tablets, sufficient to obtain a specific dose can be encapsulated in a soluble capsule.

In an alternative embodiment of the present invention the core can be prepared by wet granulation, using (if necessary) one of the binders for wet granulation, commonly used in engineering, such as pre-gelatinising starch, polyvinylpyrrolidone, a receiver array, sodium carboxymethylcellulose, alginate, potassium or sodium. The wet granulation contains the stage of the preparation of granules, suitable for tabletting by mixing the components: medicinal substance, a binder and, if necessary, substances that contribute to the grinding and filler; adding a predetermined amount of water or solvent for granulation for the formation of wet mixture; sieving the wet mixture into granules, which promotes drying; drying the wet granules to remove excess moisture; sieving the dried granules into granules suitable for tableting, and adding lubrication, one and the structure, and other excipients required for tabletting granules.

Intersolubility coating in this invention include methacrylic acid copolymer, plasticizer and sufficient NaOH to adjust the pH of the suspension. You can also apply other alkalizing agents, such as potassium hydroxide, calcium carbonate, sodium carboxymethylcellulose, magnesium oxide and magnesium hydroxide.

To get covered intersolubility sheath pharmaceutical compositions according to this invention uses a solution Intercollege coating Eudragit L-30-D55. Eudragit L 30-D55 is a water dispersion of acrylic polymer; anionic copolymer derived from methacrylic acid and ethyl acrylate, with a ratio of free carboxyl groups to ester is about 1:1 and with an average molecular weight of about 250,000, issued in the form of an aqueous dispersion containing 30 wt.% dry lacquer, and delivered by the company Rohn-Pharma Co., Germany. Because the coating is water based, it does not use any hazardous or environmentally harmful organic solvents.

Although Eudragit L-30-D55 is the preferred polymer for coating, the invention is not limited in this respect and PS NR (NRSR-NR) (USP/NF 220824), NR (NRSR-NR) (USP/NF type 200731) and HP55S, manufactured by Shin-Etsu Chemical, CoatericTM(polyvinylacetate) (use Ltd.), Sureteric f (polyvinylacetate) (use Ltd.) or AquatericTM(acetated cellulose (FMC Corp.) etc.

Intersolubility coating preferably contains a plasticizer, which is preferably diethylphthalate, although the invention is not limited in this regard and you can use other plasticizers, such as triethylcitrate (Citroflex-2), triacetin, tributylamine or polyethylene glycol.

Intersolubility coating used in this invention, it is much easier to handle than the previously described systems for coating, and particularly preferred when pokrytii particles (pellets) of small-diameter, low weight, causing small problems at work (adhesion/sort) and not requiring organic solvents.

Generally, in cases where the core contains a medicinal substance is incompatible with intersolubility coating is applied sublayer, which may contain one or more binders or plasticizers, and which behaves as a physical barrier between the core and outer layer Intercollege coverage. However, unlike R is s a new way, used in the preparation of the compositions of this invention, and adjusting the pH of the coating is not required sublayer, as the need for such an insulating layer disappears due to the increase in pH of the aqueous suspension of the coating. Since the cover is designed to disintegrate at pH 5.5, intersolubility coating when applied to pH 5 provides a relatively rapid destruction in the gut, as it would require a slight increase in alkalinity to achieve a pH of 5.5.

The preferred formulation for the preparation of tablets 50 mg without coating are presented in table. 1.

The preferred formulation for the preparation of suspensions Intercollege film coatings for the coating of tablets - 50 mg - without coating are presented in table. 2.

The percentage of ingredients (intervals) in the above formulations for tablets are uncoated and Intercollege film coating presents on the table. 3.

Pharmaceutical composition in the form of tablets with intersolubility coating can be prepared by a method which includes the stage of mixing unstable in the acidic environment of medicinal substance, a binder/filler, such as microcrystal the conditions, such as magnesium stearate, to seal in the mixer drum with the formation of a dry mix. The mixture is then prostaivaet and again placed in the mixer for re-mixing. The resulting mixture comcult or compacted, and then scatter with the formation of small granules. Then calculate the second portion of the lubricant - stearate - for tabletting and mixed in a drum mixer with the sifted granules. The resulting mixture is then formed into tablets (uncoated) with a given weight and hardness.

Then the tablets can be coated with the suspension Intercollege film coating containing Eudragit L-30-D55 and the plasticizer (diethylphthalate) in the apparatus with the upper nozzle fluidized bed coating, such as a table Aeromatic STREA-1, and then drying. In the preparation of film coating suspension to the suspension is added a solution of NaOH to pH 5,00,1. Adjusting the pH of the suspension Intercollege film coating to the value 5 and eliminates the sublayer or in the insulating layer. The advantage here is that the application Intercollege coating at pH 5 makes possible its relatively rapid degradation in the gut, as it requires only a small increase isti up to 5,4, if required for a particular recipe. Although it is preferable for the apparatus with the upper nozzle for fluidized bed, the invention is not limited in this respect, and you can also use any appropriate means of spray coating, including the apparatus with the lower nozzle or device for coating type Chan.

Depending on the size of the tablet can glottis individually, or in another embodiment, the invention can fill soluble capsules, hard shell, such as gelatin capsules of different sizes depending on the dosage of a given drug. If the pill you want to encapsulate, film-coated tablets add hydrophobic release agent (0.1 to 4 wt.%) and mix.

In the examples, preferred variants of the present invention. The following additional examples describe the materials and methods used to implement the present invention and are intended only for illustrative purposes, but in no case do not pretend to limit the scope or the spirit of this invention or the claims. All temperature maintained in degrees Celsius, unless otherwise specified, all dimensions - kolichestve prepared as described in table. 4.

Receiving ddI-tablets start putting ddI, microcrystalline cellulose, alkali starch and the first portion of magnesium stearate to seal in the drum mixer. The ingredients are mixed 102 minutes. Before mixing all the initial ingredients, containing lumps, pass through a sieve #20 mesh.

The mixture after stirring passed through sieve #40 mesh, again transferred into the drum mixer and again stirred for 102 minutes. The resulting mixture was then punched by the punch 3/4" with a smooth surface. Workpiece after forming passed through sieve #10 and #20 mesh for sorting (by sieving).

Then calculate the second portion of magnesium stearate, necessary for tableting, and bring in a drum mixer with granulation for sorting (by sieving) of grains and stirred for 102 minutes. The resulting mixture was then tabletirujut to obtain tablets of a specified weight and hardness.

To obtain a film coating in quantities sufficient for use on tablets, Eudragit L-30-D55 passed through sieve #60 mesh to remove all lumps. Filtered Eudragit weighed and then contribute with stirring in a sealed vessel containing half the quantity of water required. With the reading of the mixing vessel add diethylphthalate and continue mixing for 20 minutes or until while the homogeneity of the mixture does not become explicit. Then spend the standardization of pH meter, using buffers of pH 4 and pH 7. With continued stirring in a vessel add the NaOH solution to achieve pH values 5,00,1. Prescription weight suspension of the coating reaches adjusting the amount of water and stirring is continued for another 10 minutes.

For coating of tablets using the apparatus for operation in the fluidized bed with an upper nozzle and a suitable distribution plate, allowing the fluidization of the product (tablets) in the center.

Before coating the tablets are pre-heated in the device for applying the coating to a temperature of 45-50oC. it Was determined that the temperature at the inlet 502oWith is sufficient. Spraying speed set such as to ensure uniform coverage and satisfactory drying of the coating. It is found that the weight gain 80,5% due to film coating is sufficient. After coating, the tablets are dried for about 10 minutes when the inlet temperature of about 50oC.

It is found that the thus obtained coated intersolubility shell ddI-product protects against gastric acid (pH 3), but pre intersolubility coating is prepared as described below. ddI (50,00 mg), microcrystalline cellulose (17,00 mg), alkaline starch (2,10 mg) and the first portion of magnesium stearate to seal (0,60 mg) is loaded into the corresponding drum mixer and stirred for 102 minutes. Before mixing, if you want to get rid of lumps in the ingredients, pass through a sieve #20 mesh.

The mixture is then passed through sieve #40 mesh and again placed in a drum mixer and again stirred for 102 minutes. Then the resulting mixture was punched with 3/4" punches with smooth surface, receiving a workpiece weight of 10.2 g and a hardness of 15-20 SCU. The workpiece is then passed through sieve #10 and #20.

Then in a drum mixer with blanks make a second portion of magnesium stearate (0.3 g) for tabletting and stirred for 102 minutes. The resulting mixture was then tabletirujut using 3/16" round, smooth, glubokovodnye punches (punches) in tablets given weight when the hardness of their 3-6 SCU.

Amount (g) of the film coating suspension per 100 g for coating of tablets containing 50 mg of ddI, get, add about 50 g of water in an appropriate container with a stirrer. At a moderate speed mixing water to her slowly add 33,33 g of Eudragit L-30-D55. Before adding in the water Eudragit L-30-D55, propose complete dissolution of diethylphthalate. While mixing, slowly add a solution of sodium hydroxide (0.1 to 1 N) in order to bring the pH of the suspension to 5.0. Continuing to mix, add water to achieve the prescription weight and mix the suspension for 10 minutes.

For coating tablets used Aeromatic Table-top (STREA-1) apparatus for fluidized bed with an upper nozzle and a suitable distribution plate, such that the fluidization products (pill) occurred in the centre. Conditions of coating used in the process include the following:

Download - 250g

The temperature setting is 60oWITH

Installing the fan - 14

The temperature at the inlet - 50oWITH

The preheating time of 5 min

The deposition rate in the first 5 min to 4 g/min

The deposition rate of the final - 8 g/min

The nozzle orifice is 1.1 mm

Air volume - 120

Outlet temperature - 36oWITH

Weight gain - 8%

Final drying when installing the fan 10 - 10 min

Before the coated tablet is pre-heated in the device coating to a temperature of 45-50oC. it is Found that the temperature at the inlet 502oWith enough. The rate of intake (spraying) regulate, to ensure the coverage is enough. After coating, the tablets are dried for about 10 minutes when the inlet temperature of about 50oC.

It was found that the thus obtained ddI-product with intersolubility coating provides excellent protection against gastric acid (pH 3), but a nice selection of ddI at pH>5.

1. Pharmaceutical composition with intersolubility coating consisting of a nucleus in the form of tablets containing unstable in acid drug substance, the same as 2'3'-dideoxyinosine, pravastatin, erythromycin, digoxin, Pancreatin, 2'3'-dideoxyadenosine or 2'3'-dideoxycytidine and does not contain alkalizing agents, and Intercollege coating around the tablet, and the said coating comprises at least one alkalizing agent that increases the pH of the material Intercollege coating to minimize incompatibility Intercollege coverage and unstable in acid nucleus, moreover, the coating protects the specified kernel so that the kernel is secured at values of pH 3 or below, and at the same time is capable of releasing drug at a pH of 4.5 or above, while between the core and intersolubility coating no protective layer.

3. The pharmaceutical composition according to p. 2, characterized in that the pH of the material Intercollege coverage ranges from 4.9 to 5.4.

4. The pharmaceutical composition according to p. 2, characterized in that it is unstable in acid drug substance is a 2'3'-dideoxyinosine.

5. The pharmaceutical composition according to p. 2, characterized in that the volatile acid drug substance is pravastatin, erythromycin, digoxin, Pancreatin, 2'3'-dideoxyadenosine or 2'3'-dideoxycytidine.

6. The pharmaceutical composition according to p. 4, characterized in that the material used for forming Intercollege coating contains intersolubility covering polymer and at least one alkalizing agent that increases the pH of the material Intercollege coating to minimize incompatibility Intercollege coverage and unstable in acid nucleus.

7. The pharmaceutical composition according to p. 6, characterized in that the pH of the material Intercollege coverage ranges from 4.9 to 5.4.

8. The pharmaceutical composition according to p. 6, characterized in that modelicious akiwumi agent selected from the group consisting of potassium hydroxide, calcium carbonate, sodium carboxymethyl cellulose, magnesium oxide and magnesium hydroxide.

10. The pharmaceutical composition according to p. 6, characterized in that intersolubility covering polymer selected from the group consisting of a phthalate of hydroxypropylmethylcellulose, polivinilatsetatftalat and azettftalat pulp.

11. The pharmaceutical composition according to p. 6, characterized in that the specified intersolubility coating is a copolymer of methacrylic acid.

12. The pharmaceutical composition according to p. 11, characterized in that the specified intersolubility covering the polymer contains water dispersion of acrylic polymer anionic copolymer derived from methacrylic acid and ethyl acrylate with a ratio of free carboxyl groups to ether is about 1: 1 and with an average molecular weight of about 250,000, produced in the form of an aqueous dispersion containing 30 weight. percent dry lacquer (EudragitL 30-D55).

13. The pharmaceutical composition according to p. 11, characterized in that the specified intersolubility coating further comprises a plasticizer.

14. The pharmaceutical composition according to p. 13, characterized in that S="ptx2">

15. The pharmaceutical composition according to p. 13, characterized in that the plasticizer is diethylphthalate.

16. The pharmaceutical composition according to p. 6, wherein the core further comprises a binder.

17. The pharmaceutical composition according to p. 16, characterized in that the binder is chosen from the group consisting of sodium carboxymethylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, potassium alginate or sodium alginate.

18. The pharmaceutical composition according to p. 16, characterized in that the binder is a microcrystalline cellulose.

19. The pharmaceutical composition according to p. 16, wherein the core further comprises a lubricant.

20. The pharmaceutical composition according to p. 19, characterized in that the lubricant is a stearate.

21. The pharmaceutical composition according to p. 16, wherein the core additionally contains a substance that promotes grinding.

22. The pharmaceutical composition according to p. 21, characterized in that the substance which assists the grinding, is a Na alkaline starch, sodium-crosscarmellose, corn starch or crosslinked the STV, conducive to grinding, is a Na-alkaline starch.

24. The pharmaceutical composition according to p. 6, having the following composition, %:

Core

Drugs (didanosine) - 15-97,5

Microcrystalline cellulose - 0-40

Na-alkaline starch - 0-6

Magnesium stearate - 0-3

The coating Eudragit L-30-D55 - 2-30

Diethylphthalate - 0,5-6,0

25. The pharmaceutical composition according to p. 6, wherein the tablet contains 2', 3'-dideoxyinosine in number, admission which twice a day achieved daily dose.

26. The pharmaceutical composition according to p. 6, wherein the tablet contains 2', 3'-dideoxyinosine in an amount corresponding to a daily dose, taken once a day.

27. A method of obtaining a pharmaceutical composition with intersolubility coating containing stage (a) mixing unstable in acid drugs, such as 2', 3'-dideoxyinosine, pravastatin, erythromycin, digoxin, Pancreatin, 2'3'-dideoxyadenosine or 2', 3'-dideoxycytidine and optional components, except alkalizing agents, mixture, suitable for tabletting, (b) tableting the above-mentioned mixture with getting the kernel in the form of a t the material Intercollege coating to minimize incompatibility Intercollege coverage and unstable in acid nucleus, and (g) applying the specified material Intercollege coating on the tablet core.

28. The method according to p. 27, characterized in that the mixture contains unstable in acid drug substance, a binder and a lubricant.

29. The method according to p. 27, characterized in that the volatile acid drug substance is a 2', 3'-dideoxyinosine.

30. The method according to p. 27, characterized in that the volatile acid drug substance is pravastatin, erythromycin, digoxin, Pancreatin, 2', 3'-dideoxyadenosine or 2', 3'-dideoxycytidine.

31. The method according to p. 29, further comprising a stage screening core tablets with retention of nuclei for further coating having approximately from # 10 to # 20 mesh.

32. The method according to p. 29, characterized in that the tablets have a hardness 3-6 SCU.

33. The method according to p. 29, characterized in that the receipt of the coating additionally includes the stage of (a) mixing Intercollege covering polymer with water to form a mixture of the polymer/water, (b) mixing a plasticizer with the mixture obtained in stage (a) and (b) mixing alkalizing agent with the mixture, poluce stage coating additionally includes the stage of (a) pre-heating of these tablets in the apparatus for deposition in the fluidized bed until about 45-50o(B) spraying on these pills specified coverage, and (C) drying these pills.

35. The method according to p. 29, characterized in that the binder is a microcrystalline cellulose.

36. The method according to p. 29, characterized in that the lubricant is a stearate.

37. The method according to p. 29, characterized in that the substance which assists the grinding, is an alkaline starch.

38. The method according to p. 29, wherein the specified intersolubility floor contains methacrylic acid copolymer and a plasticizer.

39. The method according to p. 38, characterized in that the plasticizer is diethylphthalate.

40. The method according to p. 38, characterized in that the methacrylic acid copolymer is a Eudragit L-30-D55.

 

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