RU2522897C1 - Solid enteric oral dosage form of proinsulin c-peptide (versions) and method for preparing it (versions) - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: in the form of tablets, a core of which contains at least, wt %: proinsulin C-peptide - 0.01-5.0, hydroxypropyl cellulose - 1.0-6.0, or hydroxypropyl methylcellulose - 1.0-10.0, or polyvinyl pyrrolidone - 1.0-5.0, magnesium stearate - 0.01-1.0, colloidal silicone dioxide - 0.01-10.0, talc - 0.01-3.0, microcrystalline cellulose - the rest, while a coating represents an enteric film coating containing, wt %: talc - 10.0-20.0, titanium dioxide - 5.0-15.0, triethyl citrate - 7.0-14.0, silicone dioxide - 0.2-2.2, poly(methacrylic acid) - the rest. According to the other version, in the form of capsules a core of which contains at least, wt %: proinsulin C-peptide - 0.01-5.0, hydroxypropyl cellulose - 1.0-10.0, or hydroxypropyl methylcellulose - 1.0-10.0, or polyvinyl pyrrolidone - 1.0-5.0, microcrystalline cellulose - the rest, while the coating consists of an enteric film coating which contains, wt %: talc - 10.0-20.0, titanium dioxide - 5.0-15.0, triethyl citrate - 7.0-14.0, silicone dioxide - 0.2-2.2, poly(methacrylic acid) - the rest, and a solid capsule which contains, wt %: titanium dioxide - 0.1-5.0 and gelatin - up to 100. According to the other version of the capsules, the coating consists of a solid capsule which contains, wt %: titanium dioxide - 1.0-2.0, gellan gum - 1.0-5.0 and hydroxypropyl methylcellulose - the rest. There are also disclosed methods for preparing these dosage forms.

EFFECT: pre-set release of the active substance and maintained stability.

24 cl, 7 ex, 15 tbl

Description

The invention relates to the field of pharmacology and the pharmaceutical industry, namely to the development and manufacture of a solid enteric dosage form of the known pro-insulin C-peptide intended for oral use.

The human proinsulin C-peptide (connecting peptide) is a peptide consisting of 31 amino acids with the following sequence: EAEDLQVGQVELGGGPGAGSLQPLALEGSLQ. The C-peptide is an indicator of the formation of insulin from proinsulin in the beta cells of the pancreatic islets of Langerhans. Insulin and the C-peptide are the end products of the conversion of proinsulin as a result of exposure to endopeptidase.

The possibility of using the pro-insulin C peptide covalently immobilized on a water-soluble polymer selected from the group consisting of polyethylene oxide, polyvinyl pyrrolidone, isoprenol, dextran, polyacrylamide, polyurethane for the treatment and prevention of diabetic complications in diabetes mellitus, in particular diabetic neuropathy (retropathy, neuropathy, RF patent 2413531, RF application 2007137048). However, the specific compositions of the solid forms of proinsulin C-peptide intended for oral use are not described in these sources of information.

The possibility of oral administration of proinsulin C-peptide for the treatment of diabetes and / or diabetic complications (patent EP 1675611, International application WO 2005039627) in the form of a composition containing the proinsulin C-peptide itself in powder form together with at least one pharmaceutically acceptable is also described. carrier or excipient, preferably enclosed in an enterocapsule to protect against degradation of the peptide in the stomach, thereby providing absorption of the active substance from the gums or in the small intestine. However, the specific compositions of tablets or capsules containing proinsulin C-peptide and intended for oral administration are also not disclosed in these sources of information.

WO 2009068911 describes the possibility of using proinsulin C-peptide for the prevention and treatment of macrovascular complications in diabetes. The possibility of creating an oral composition comprising a proinsulin C peptide and a suitable diluent, excipient or carrier is indicated. However, neither in the description of the invention, nor in the examples of specific implementation, no real composition of the solid enteric-soluble form of the proinsulin C-peptide intended for oral administration is given.

Known compositions (RF patent 2206336) in the form of sublingual tablets and enterocapsules suitable for oral use, which include active fragments / peptides of the proinsulin C-peptide molecule in the form of a sterile purified finished powder, preferably coated with a protective film or films (enterocapsules) to protect against destruction active peptides in the stomach, thereby providing the possibility of absorption of these substances from the gums or in the small intestine. As excipients for sublingual tablets or enterocapsules, the composition contains lactose and unsolved (undefined) components in the patent of the Russian Federation 2206336. The composition of the protective film and enterocapsules is also not disclosed.

A known pharmaceutical composition (RF patent 2433830), comprising a mixture of the C-peptide of proinsulin, aromatic alcohol, an absorption enhancer selected from propyl gallate, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA) and their analogues and derivatives, or mixtures thereof; and biguanide or a pharmaceutically acceptable salt thereof. This mixture may be in the form of tablets or gelatin-coated enterocapsules. However, it is known that bottled hydroxytoluene - Butylated Hydroxytoluene (BHT) and bottled hydroxyanisole - Butylated Hydroxyanisole (BHA), E320 are carcinogens that persist for a long time in tissues (http://dobroweb.ru/secrets/l 139; http: // dobroweb .ru / secrets / 448). E310 - Propyl gallate - banned for use in food for infants and young children, as it can cause indigestion, skin irritation (http://kidsleam.ru/blogs/vospitanie-detei/chto-popadaet-v-nas-ili -ostorozhno-vrednie-produkti-9.html), in addition, it is known that propyl gallate has an effect on the body similar to the action of female sex hormones estrogen, causes asthma, stomach irritation and causes allergic skin rashes. Also, caution should be taken with propyl gallates for people who are highly sensitive to aspirin (http://www.novostioede.ru/food)_additive/e3xx-antioksidantv/e310_propilgallat/). All this limits the possibility of using the pharmaceutical composition according to the patent of the Russian Federation 2433830. In addition, the description does not show any real composition of the solid enteric form of proinsulin C-peptide intended for oral administration of the preparation, and no specific example of the preparation of such forms is disclosed.

The objective of the invention is to develop a solid enteric dosage form of proinsulin C-peptide, acceptable for oral use, and thereby expanding the arsenal of drugs for the treatment of diabetes and the treatment and prevention of diabetic complications of domestic production.

In addition, the composition providing a solid enteric dosage form of the pro-insulin C-peptide should have a simple composition and not include any excipients that are toxicologically toxic.

Another objective is to enable the immediate release or prolonged action of the active substance in a slightly alkaline environment of the intestine at a pH of 6.5-7.0.

Another objective is to ensure the stability of the active substance during storage of finished dosage forms in a domestic refrigerator at positive temperatures.

The tasks are solved by the fact that a solid enteric-soluble dosage form of proinsulin C-peptide for oral administration is proposed, consisting of a core comprising proinsulin C-peptide and excipient as an active substance and a coating coating thereof made in the form of tablets, the core of which as excipients contains microcrystalline cellulose, polyvinylpyrrolidone or a cellulose derivative selected from the group consisting of hydroxypropyl cellulose and hydroxypropyl methyl cellulose, magnesium stearate, silicon colloidal silica and talc, the following component ratio, wt.%:

Proinsulin C peptide - 0.01-5.0

hydroxypropyl cellulose - 1.0-6.0

or hydroxypropyl methylcellulose - 1.0-10.0

or polyvinylpyrrolidone - 1.0-5.0

magnesium stearate - 0.01-1.0

silicon dioxide colloidal - 0.01-10.0

talc - 0.01-3.0

microcrystalline cellulose - up to 100,

and the shell is an enteric film coating containing a copolymer of methacrylic and acrylic acids, talc, titanium dioxide, triethyl citrate, silicon dioxide, in the following ratio, wt.%:

talc - 10.0-20.0

titanium dioxide - 5.0-15.0

triethyl citrate -7.0-14.0

silicon dioxide - 0.2-2.2

copolymer of methacrylic and acrylic acids - up to 100.

In the particular case of tablets, the core as excipients additionally contains at least one component selected from the group of mannitol or sorbitol, cyclodextrin or lecithin, in the following ratio, wt.%:

Proinsulin C peptide - 0.01-5.0

hydroxypropyl cellulose - 1.0-6.0

or hydroxypropyl methylcellulose - 1.0-10.0

or polyvinylpyrrolidone - 1.0-5.0

mannitol - 1-90.0

or sorbitol - 1-90.0

cyclodextrin - 0.03-15.0

or lecithin - 0.03-15.0

magnesium stearate - 0.01-1.0

silicon dioxide colloidal - 0.01-10.0

talc - 0.01-3.0

microcrystalline cellulose - up to 100.

To ensure the prolonged action of the proinsulin C-peptide, the core contains the following ratio of components, wt.%:

Proinsulin C-peptide - 0.01-5.0

hydroxypropyl methylcellulose - 1.0-80.0

optionally hydroxypropyl cellulose - 1.0-35.0

or optionally polyvinylpyrrolidone - 1.0-5.0

magnesium stearate - 0.01-1.0

silicon dioxide colloidal - 0.01-10.0

talc - 0.01-3.0

microcrystalline cellulose - up to 100.

In the particular case of tablets providing the prolonged action of the proinsulin C-peptide, the core additionally contains at least one component selected from the group consisting of mannitol or sorbitol, cyclodextrin or lecithin, ethyl cellulose or sodium alginate, in the following ratio, wt. %:

Proinsulin C peptide - 0.01-5.0

hydroxypropyl cellulose - 1.0-35.0

or hydroxypropyl methylcellulose - 1.0-80.0

or polyvinylpyrrolidone - 1.0-5.0

mannitol - 1.0-90.0

or sorbitol - 1.0-90.0

cyclodextrin - 0.03-15.0

or lecithin - 0.03-15.0

ethyl cellulose - 1.0-20.0

or sodium alginate - 0.1-10.0

magnesium stearate - 0.1-1.0

silicon dioxide colloidal - 0.1-10.0

talc - 0.1-3.0

microcrystalline cellulose - up to 100.

Another variant of the solid enteric-soluble dosage form of the pro-insulin C-peptide for oral use is presented in the form of capsules, the core of which contains microcrystalline cellulose, polyvinylpyrrolidone or a cellulose derivative selected from the group consisting of hydroxypropyl cellulose and hydroxypropylmethyl cellulose as excipients. %:

Proinsulin C peptide - 0.01-5.0

hydroxypropyl cellulose - 1.0-10.0

or hydroxypropyl methylcellulose - 1.0-10.0

or polyvinylpyrrolidone - 1.0-5.0

microcrystalline cellulose - up to 100,

and the shell consists of an enteric film coating and a hard capsule, the enteric film coating containing a copolymer of methacrylic and acrylic acids, talc, titanium dioxide, triethyl citrate, silicon dioxide, in the following ratio, wt.%

talc - 10.0-20.0

titanium dioxide - 5.0-15.0

triethyl citrate - 7.0-14.0

silicon dioxide - 0.2-2.2

copolymer of methacrylic and acrylic acids - up to 100,

and the hard capsule contains gelatin and titanium dioxide in the following ratio, wt.%:

titanium dioxide - 0.1-5.0

gelatin - up to 100.

In the particular case of capsules, the core additionally contains cyclodextrin or lecithin, in the following ratio, wt.%:

Proinsulin C peptide - 0.01-5.0

hydroxypropyl cellulose - 1.0-10.0

or hydroxypropyl methylcellulose - 1.0-10.0

or polyvinylpyrrolidone - 1.0-5.0

cyclodextrin - 0.03-15.0

or lecithin - 0.03-15.0

microcrystalline cellulose - up to 100.

To ensure the prolonged action of the proinsulin C-peptide, the core of the capsules contains the following ratio of components, wt.%:

Proinsulin C peptide - 0.01-5.0

hydroxypropyl methylcellulose - 1.0-80.0

optionally hydroxypropyl cellulose - 1.0-35.0

or optionally polyvinylpyrrolidone - 1.0-5.0

microcrystalline cellulose - up to 100.

In the particular case of capsules providing the prolonged action of the proinsulin C-peptide, the core additionally contains at least one component selected from the group comprising cyclodextrin or lecithin, ethyl cellulose or sodium alginate, in the following ratio, wt.%:

Proinsulin C peptide - 0.01-5.0

hydroxypropyl cellulose - 1.0-35.0

or hydroxypropyl methylcellulose - 1.0-80.0

or polyvinylpyrrolidone - 1.0-5.0

cyclodextrin - 0.03-15.0

or lecithin - 0.03-15.0

ethyl cellulose - 1.0-20.0

or sodium alginate - 0.1-10.0

microcrystalline cellulose - up to 100.

Another variant of the solid enteric-soluble dosage form of proinsulin C-peptide for oral use in the form of capsules, the core of which as excipients contains microcrystalline cellulose, polyvinylpyrrolidone or a cellulose derivative selected from the group consisting of hydroxypropyl cellulose and hydroxypropyl methyl cellulose, in the following ratio:%, is obtained.

Proinsulin C peptide - 0.01-5.0

hydroxypropyl cellulose - 1.0-10.0

or hydroxypropyl methylcellulose - 1.0-10.0

or polyvinylpyrrolidone - 1.0-5.0

microcrystalline cellulose - up to 100,

and the shell is a solid enteric capsule containing gelatin, titanium dioxide, gellan gum and hydroxypropyl cellulose in the following ratio, wt.%:

titanium dioxide - 1.0-2.0

gellan gum - 1.0-5.0

hydroxypropyl methylcellulose - up to 100.

In the particular case of the execution of these capsules, the core additionally contains cyclodextrin or lecithin, in the following ratio of components, wt.%:

Proinsulin C peptide - 0.01-5.0

hydroxypropyl cellulose - 1.0-10.0

or hydroxypropyl methylcellulose - 1.0-10.0

or polyvinylpyrrolidone - 1.0-5.0

cyclodextrin - 0.03-15.0

or lecithin - 0.03-15.0

microcrystalline cellulose - up to 100.

To ensure the prolonged action of the proinsulin C-peptide, the core of the capsules contains the following ratio of components, wt.%:

Proinsulin C-peptide - 0.01-5.00

hydroxypropyl methylcellulose - 1.0-80.0

optionally hydroxypropyl cellulose - 1.0-35.0

or optionally polyvinylpyrrolidone - 1.0-5.0

microcrystalline cellulose - up to 100.

In the particular case of capsules providing a prolonged action of the pro-insulin C-peptide, the core additionally contains at least one component selected from the group comprising cyclodextrin or lecithin, ethyl cellulose or sodium alginate, in the following ratio, wt.%:

Proinsulin C peptide - 0.01-5.0

hydroxypropyl cellulose - 1.0-35.0

or hydroxypropyl methylcellulose - 1.0-80.0

or polyvinylpyrrolidone - 1.0-5.0

cyclodextrin - 0.03-15.0

or lecithin - 0.03-15.0

ethyl cellulose -1.0-20.0

or sodium alginate - 0.1-10.0

microcrystalline cellulose - up to 100.

The problem is also solved by the fact that the proposed method of obtaining a solid enteric dosage form of proinsulin C-peptide for oral use in the form of tablets, which consists in mixing an aqueous solution of pro-insulin C-peptide with a carrier - at least microcrystalline cellulose, the resulting mixture is moistened with water With a solution of hydroxypropyl cellulose or hydroxypropyl methyl cellulose or polyvinylpyrrolidone, granules are formed, which are dried at a temperature not exceeding 35 ° C, calibrated and dusted talc, magnesium stearate and silicon dioxide colloidal dioxide, then kernels are formed from dried granules in the form of tablets, which are dedusted and enteric coated with a film coating by spraying an aqueous suspension containing a copolymer of methacrylic and acrylic acids, talc, titanium dioxide, triethyl citrate and silicon dioxide , to increase the weight of the tablets by 4-10%.

In the particular case of the preparation of tablets, an aqueous solution of the pro-insulin C peptide is pre-mixed with an aqueous solution of cyclodextrin or lecithin, and mannitol or sorbitol is additionally added as a carrier.

To obtain tablets that provide the prolonged action of the pro-insulin C-peptide, hydroxypropyl methylcellulose is additionally added as a carrier.

In the particular case of obtaining tablets that provide a prolonged action of the proinsulin C peptide, an aqueous solution of the proinsulin C peptide is pre-mixed with an aqueous solution of cyclodextrin or lecithin, and in the process of granule formation, an aqueous solution of sodium alginate or ethyl cellulose is additionally applied immediately after drying.

In another embodiment, the stated problem is solved by the fact that a method for producing a solid enteric-soluble dosage form of a pro-insulin C peptide for oral administration in the form of capsules is provided, wherein the aqueous solution of the pro-insulin C peptide is mixed with an aqueous solution of hydroxypropyl cellulose or hydroxypropyl methyl cellulose or polyvinylpyrrolidone obtained the solution is sprayed onto a carrier - at least microcrystalline cellulose, and the nuclei are formed in the form of pellets, which are dried at a temperature of exceeding 35 ° C, then enteric coating film is applied to the pellet cores by spraying an aqueous suspension containing a copolymer of methacrylic and acrylic acids, talc, titanium dioxide, triethyl citrate, silicon dioxide, until the pellet mass is increased by 4-10%, and then coated an enteric film coating the pellets are encapsulated in capsules containing gelatin and titanium dioxide. In the particular case of capsules, cyclodextrin or lecithin is additionally added to the aqueous solution of the proinsulin C-peptide.

In order to obtain capsules providing the prolonged action of the pro-insulin C-peptide, hydroxypropyl methylcellulose is additionally added as a carrier.

In the particular case of the preparation of capsules providing the prolonged action of the proinsulin C peptide, cyclodextrin or lecithin is additionally added to the aqueous solution of the proinsulin C peptide, hydroxypropyl methylcellulose is additionally added as a carrier, and an aqueous solution of sodium alginate is additionally coated on the dried pellets with an enteric film coating or ethyl cellulose.

Another solution to the problem is proposed by the fact that another method is proposed for preparing a solid enteric-soluble dosage form of proinsulin C-peptide for oral administration in capsule form, which consists in mixing an aqueous solution of proinsulin C-peptide with an aqueous solution of hydroxypropyl cellulose or hydroxypropyl methyl cellulose, or polyvinylpyrrolidone, the resulting mixture is applied by spraying on a carrier - at least microcrystalline cellulose, and form kernels in the form of pellets, which are dried At a temperature not exceeding 35 ° C, they are then encapsulated in capsules containing titanium dioxide, gellan gum and hydroxypropyl methylcellulose.

In the particular case of the implementation of this method of producing capsules in an aqueous solution of the C-peptide of proinsulin, cyclodextrin or lecithin is additionally added.

In order to obtain capsules providing the prolonged action of the pro-insulin C-peptide, hydroxypropylmethyl cellulose is additionally added as a carrier.

In another particular case of obtaining capsules providing the prolonged action of the proinsulin C peptide, cyclodextrin or lecithin is additionally added to the aqueous solution of the proinsulin C peptide, hydroxypropyl methyl cellulose is additionally added as a carrier, and an aqueous solution of sodium alginate or ethyl cellulose is additionally applied to the dried pellets before encapsulation .

The choice of carrier for the active component of the pro-insulin C-peptide (C-peptide) was carried out on the basis of the following conditions: it must be highly compressible and have good flowability. The specified properties to one extent or another have many accepted in this field media. However, microcrystalline cellulose (MCC) and hydroxypropyl methyl cellulose in combination with other components of the claimed composition made it possible to achieve the required release rate of the C-peptide from the dosage form.

To improve the permeability of the C-peptide through the wall of the gastrointestinal tract, lecithin or cyclodextrin was introduced into the composition of the oral dosage form.

As binders, polyvinylpyrrolidone, hydroxypropyl cellulose and hydroxypropyl methyl cellulose were selected, which provide the ability to adhere auxiliary substances and the active component during granulation and, as a result, ensure granular mixture flowability and tablet strength. The selected binders have the necessary properties, both in the dry state and in the form of solutions, they are easily soluble in water and allow you to adjust the rate of release of the C-peptide from the dosage form.

Talc, colloidal silicon dioxide and magnesium stearate were used as dusting agents to protect the press tool from sticking of the tablet mass onto the walls of the punches and dies and to give the tablet mass fluidity.

The main problem of the oral administration of the C-peptide is its instability in the acidic environment of the stomach and its destruction under the action of proteolytic enzymes located there. To solve this problem, tablets or granules of the C-peptide were coated with an enteric coating, thereby ensuring the release of the active component in the gastrointestinal tract, the environment of which is the least destructive for the peptide.

The qualitative composition and quantitative ratios of the components claimed as the present invention result in the preparation of the proposed solid dosage forms of the C-peptide that meet all the requirements of GP XI, the high manufacturability of their production using available excipients, while ensuring the necessary release rate of the active substance from the finished dosage form .

The proposed method provides the complete mechanization of the manufacturing process, its high productivity, cleanliness and hygiene, dosing accuracy and the set release rate of the active substance, good stability of the solid dosage form during storage.

In order to determine the kinetics of C-peptide release in vitro, the generally accepted pharmacopeia method “Dissolution, Method I” described in OFS 42-0135-09 was used.

The following requirements apply to capsule formulations:

- uniformity of dosage - uniformity (uniformity) of the distribution of the active substance in capsules. The content of the active substance in one capsule can deviate no more than ± 15% of the average value;

- solubility - the ability to dissolve in a timely manner. The following standards have been established for the modified immediate release dosage form: not more than 5% C-peptide should dissolve in a 0.1 M hydrochloric acid solution in 120 minutes; at least 75% of the C-peptide should dissolve in a phosphate buffer solution with a pH of 6.8 in 45 minutes. The following norms have been established for the modified dosage form of prolonged action: not more than 5% of the C-peptide should dissolve in a 0.1 M solution of hydrochloric acid in 120 minutes; not more than 50% of the C-peptide should dissolve in a phosphate buffer solution with a pH of 6.8 in 60 minutes and at least 75% in 240 minutes.

The following examples of specific implementation provide a solid form of the C-peptide of proinsulin in the form of capsules that meet the established requirements.

The following requirements apply to medicines in the form of tablets:

- uniformity of dosage - uniformity (uniformity) of the distribution of the active substance in tablets. The content of the active substance in one tablet can deviate no more than ± 15% of the average value;

- solubility - the ability to dissolve in a timely manner. The following standards have been established for the modified immediate release dosage form: not more than 5% C-peptide should dissolve in a 0.1 M hydrochloric acid solution in 120 minutes; at least 75% of the C-peptide should dissolve in a phosphate buffer solution with a pH of 6.8 in 45 minutes. The following norms have been established for the modified dosage form of prolonged action: not more than 5% of the C-peptide should dissolve in a 0.1 M solution of hydrochloric acid in 120 minutes; not more than 50% of the C-peptide should dissolve in a phosphate buffer solution with a pH of 6.8 in 60 minutes and at least 75% in 240 minutes;

- mechanical fracture strength and abrasion resistance. The specified test is carried out for tablet cores (not coated with an enteric coating). The mechanical fracture strength of the tablet cores should be at least 70 kN, and the abrasion resistance should be at least 99%.

The following specific examples of implementation provide a solid form of proinsulin C-peptide in the form of tablets, which also meet the established requirements.

The proposed solid forms in the form of tablets and capsules of immediate release and prolonged action are more convenient for administration and more stable during storage than suspensions or sprays.

The invention is further illustrated by the following examples, which should not be interpreted as limiting the scope of the invention.

Example 1: Preparation of a solid enteric-soluble dosage form of a modified-release proinsulin C peptide using an enteric film coating and hard gelatin capsules as a coating

To obtain a solid enteric dosage form of the pro-insulin C-peptide with modified release of the active substance using an enteric film as a coating

coatings and hard gelatin capsules used the method of applying the active substance to an inert carrier (for example, microcrystalline cellulose) using a fluidized bed apparatus. The manufacturing technology of the dosage form of the C-peptide involves weighing the ingredients, including the active compound - proinsulin C-peptide (C-peptide) and most excipients (e.g. hydroxypropyl cellulose, polyvinylpyrrolidone, hydroxypropyl methyl cellulose), directly applying the active substance (proinsulin C-peptide) with adding a liquid binding solution containing hydroxypropyl cellulose (or polyvinyl pyrrolidone or hydroxypropyl methyl cellulose) to an inert carrier, pellet formation, pre representing the core of the claimed solid enteric dosage form of proinsulin C-peptide, drying them at a temperature of 30 ° C, pellet coating with an enteric film coating. The enteric coating contains a copolymer of methacrylic acid - 60.80%, talc - 15.20%, titanium dioxide - 12.16%, triethyl citrate - 10.64%, silicon dioxide - 1.20% and, in the particular case of implementation, represents finished film coating, for example, the company "Ashland".

The advantage of this method includes reducing the amount of excipients used, the beneficial distribution of the active substance on an inert carrier, reducing dust and aerosol contaminants and preventing the separation of components.

Suitable amounts of substances for each batch of capsules were calculated according to the target contents per unit dose, as shown in Table 1.

Coated with an enteric film coating, the pellets were encapsulated in hard gelatin capsules containing gelatin - 98% and titanium dioxide - 2%, and, in the particular case of implementation, which are ready-made capsules, for example, Capsugel.

The ratio of the mass of the core (pellet) and the mass of the film coating is approximately 17: 1, respectively.

The ratio of the weight of the coated pellets to the weight of the capsules is approximately 3.4: 1, respectively.

Thus, the ratio of the mass of the nucleus to the mass of the enteric film coating and to the mass of the capsule is about 3.2: 0.2: 1.0.

Table 1 Ingredient Drug A [mg / capsule] Drug B [mg / capsule] Drug C [mg / capsule] Drug D [mg / capsule] Drug E [mg / capsule] Drug F [mg / capsule] Proinsulin C Peptide 0.5 1,0 1,0 2.0 3.0 5,0 Hydroxypropyl cellulose - - 5.7 - - 3.9 Polyvinylpyrrolidone - 5.5 - 4,5 - - Hydroxypropyl methylcellulose 6D - - - 5.2 - Microcrystalline cellulose 315.2 315.3 315.1 315.3 313.6 312.9 Enteric coating 18.2 18.2 18.2 18.2 18.2 18.2 The mass of the contents of the capsule 340.0 340.0 340.0 340.0 340.0 340.0 Continuation of table 1 Ingredient Drug G [mg / capsule] Drug H [mg / capsule] Drug J [mg / capsule] Drug K [mg / capsule] Drug L [mg / capsule] Drug M [mg / capsule] Proinsulin C peptide 0.5 1,0 1,0 2.0 3.0 5,0 Hydroxypropyl cellulose - - 5.7 - - 3.9 Polyvinylpyrrolidone - 5.5 - 4,5 - - Hydroxypropyl methylcellulose 6.1 - - - 5.2 - Cyclodextrin 1.3 - 2,3 - 7.8 - Lecithin - 2,5 - 5.2 - 8.8 Microcrystalline cellulose 313.9 312.8 312.8 310.1 305.8 304.1 Enteric coating 18.2 18.2 18.2 18.2 18.2 18.2 The mass of the contents of the capsule 340.0 340.0 340.0 340.0 340.0 340.0

The release of the drug from the modified release hard gelatin capsules to program the place of release of the drug substance:

For capsules prepared according to Example 1, drug release profiles were determined using a paddle-type dissolution device, and the stirrer was rotated at 50 rpm. The tests were carried out in two stages:

1st stage (acid). Dissolution medium - 0.1 M solution of hydrochloric acid. The volume of the dissolution medium is 900 ml. The test duration is 2 hours.

2nd stage (alkaline). The dissolution medium is a 0.2 M solution of sodium phosphate (Na ₃ PO ₄ · 12H ₂ O) having a pH value of 6.8 ± 0.05. The volume of the dissolution medium is 500 ml. The solution during the experiment was selected for analysis in portions of 15 ml after 120, 130, 140, 160, 205 and 240 min from the start of the experiment. After selection of an aliquot, the dissolution medium in the beaker was not replenished. When calculating the amount of C-peptide transferred to the solution, the change in the volume of the dissolution medium was taken into account. The quantification of the C-peptide in the buffer solution was carried out by HPLC. The results of the study are presented in Table 2.

table 2 Time (min) The amount of C-peptide transferred to the solution,% Drug A Drug C Drug D Drug F Drug G Drug H Drug J Drug L 0 0 0 0 0 0 0 0 0 120 1,5 2.1 2.0 1.9 1.7 1,0 1.9 1,2 130 10.3 13.0 12.7 12.7 12.5 11.9 12.8 12.1 140 70 76 68 73 70 65 61 64 160 82 86 79 83 87 85 87 80 205 93 89 87 91 94 93 93 92 240 94 92 90 93 95 90 96 95

The results obtained, presented in table 2, allow us to argue about the effective resistance of the dosage form to the environment of the stomach and the rapid release of the C-peptide from the dosage form into a buffer solution (pH 6.8), which simulates the intestinal environment. Tests to determine the release profile of the active substance mimic the process of LF passage through the gastrointestinal tract: acid stage (within 120 minutes) - stomach, alkaline stage - intestines. The conclusion about the immediate release of the active substance is made on the basis of the results obtained by the alkaline stage, since solid dosage forms from which the active substance is released within 45 minutes in an amount of at least 75% relate to immediate release dosage forms. Thus, the developed dosage form eliminates the destruction of the C-peptide in the acidic environment of the stomach and under the action of proteolytic enzymes in it.

Example 2: Preparation of a solid enteric-soluble dosage form of a modified-release proinsulin C-peptide using an enteric-coated capsule as a shell

A solid enteric dosage form of the pro-insulin C-peptide with modified release of the active substance using enteric capsules as an envelope was prepared by applying the active substance to an inert carrier using a fluidized bed apparatus that includes weighing ingredients including the active compound and most excipients, direct application of the active substance with the addition of a liquid binding solution on an inert carrier, drying at a temperature of 30 ° C of the obtained pellets, which are the core of a solid dosage form, coated with the active substance using a fluidized bed granulator dryer (mod. V-2.5 of the Ventilus series). The advantage of this method includes reducing the amount of excipients used, the useful distribution of the active substance on an inert carrier, reducing dust and aerosol contaminants and preventing the separation of components.

Suitable amounts of substances for each batch of capsules were calculated according to the target contents per unit dose, as given in Table 3.

Pellets were encapsulated in hard enteric-soluble capsules of DRCaps containing hydroxypropyl methylcellulose - 93.1%, titanium dioxide - 1.9%, gellan gum - 5.0%, and in the particular case they are ready-made capsules, for example, Capsugel.

The ratio of the weight of the coated pellets to the weight of the capsules is approximately 3.4: 1, respectively.

Table 3 Ingredient Drug A [mg / capsule] Drug B [mg / capsule] Drug C [mg / capsule] Drug D [mg / capsule] Drug E [mg / capsule] Drug F [mg / capsule] Proinsulin C Peptide 0.5 1,0 1,0 2.0 3.0 5,0 Hydroxypropyl cellulose - - 5.7 - - 3.9 Polyvinylpyrrolidone - 5.5 - 4,5 - - Hydroxypropyl methylcellulose 6.1 - - - 5.2 - Microcrystalline cellulose 333,4 333.5 333.3 333.5 331.8 331.1 The mass of the contents of the capsule 340.0 340.0 340.0 340.0 340.0 340.0 Continuation of table 3 Ingredient Drug G [mg / capsule] Drug H [mg / capsule] Drug J [mg / capsule] Drug K [mg / capsule] Drug L [mg / capsule] Drug M [mg / capsule] Proinsulin C Peptide 0.5 1,0 1,0 2.0 3.0 5,0 Hydroxypropyl cellulose - - 5.7 - - 3.9 Polyvinylpyrrolidone - 5.5 - 4,5 - - Hydroxypropyl methylcellulose 6.1 - - - 5.2 - Cyclodextrin 1.3 - 2,3 - 7.8 - Lecithin - 2,5 - 5.2 - 8.8 Microcrystalline cellulose 332.1 331.0 331.0 328.3 324.0 322.3 The mass of the contents of the capsule 340.0 340.0 340.0 340.0 340.0 340.0

Solid enteric drug release

modified release capsules:

For capsules prepared according to Example 2, drug release profiles were determined using a paddle-type dissolution apparatus, stirrer rotation speed of 50 rpm. The tests were carried out in two stages:

1st stage (acid). Dissolution medium - 0.1 M solution of hydrochloric acid. The volume of the dissolution medium is 900 ml. The test duration is 2 hours.

2nd stage (alkaline). The dissolution medium is a 0.2 M solution of sodium phosphate (Na ₃ PO ₄ · 12H ₂ O) having a pH value of 6.8 ± 0.05. The volume of the dissolution medium is 500 ml. The solution during the experiment was selected for analysis in 15 ml portions after 120, 130, 140, 160, 205 and 240 min from the start of the experiment; after the aliquot was taken, the dissolution medium in the beaker was not replenished. When calculating the amount of C-peptide transferred to the solution, the change in the volume of the dissolution medium was taken into account. Quantification of the C-peptide in the buffer solution was carried out by HPLC. The research results are presented in Table 4.

Table 4 Time (min) The amount of C-peptide transferred to the solution,% Drug A Drug C Drug D Drug F Drug G The drug N Drug J Drug L 0 0 0 0 0 0 0 0 0 120 0.8 0.9 1,1 0.9 0.9 1,2 1,2 1,1 130 2,5 3.3 2,5 2,4 2.7 1.9 2,4 2.0 140 72 74 70 71 68 69 65 63 160 84 87 77 82 85 81 84 75 205 93 92 85 89 93 94 90 86 240 95 94 90 92 95 97 92 90

The results obtained allow us to argue about the effective resistance of the dosage form to the environment of the stomach and the immediate release of the C-peptide from the dosage form into a buffer solution (pH 6.8), which simulates the intestinal environment.

Thus, the developed dosage form eliminates the destruction of the C-peptide in the acidic environment of the stomach and under the action of proteolytic enzymes in it.

Example 3: Obtaining a solid enteric-soluble dosage form of a modified-release proinsulin C-peptide using a enteric-coated film coating and sustained release C-peptide hard gelatin capsules (sustained release) as a shell

For the preparation of dosage forms of proinsulin C-peptide

prolonged action (delayed release), the method of granulation in the fluidized bed of the active substance and substances that provide a slow release (for example,

hydroxypropyl methylcellulose), which includes weighing the ingredients, including the active compound and most excipients, preparing solutions of binders (for example, cellulose derivatives or polyvinylpyrrolidone), granulation in a fluidized bed and drying granules (pellets) at a temperature of 30 ° C, coating the resulting granules (pellets) with an enteric film coating, using a fluid bed dryer granulator (mod. U-2.5 of the Ventilus series). The advantage of this method includes reducing the amount of excipients used, the useful distribution of the active substance on an inert carrier, reducing dust and aerosol contaminants and preventing the separation of components.

Suitable amounts of substances for each batch of capsules were calculated according to the target contents per unit dose, as shown in Table 5.

The enteric coating contains a copolymer of methacrylic acid - 60.80%, talc - 15.20%, titanium dioxide - 12.16%, triethyl citrate - 10.64%, silicon dioxide - 1.20%) and, in the particular case of implementation, represents a ready-made film coating, for example, by Ashland. The ratio of the mass of the core (pellet) and the mass of the film coating is approximately 17: 1, respectively.

Coated with an enteric film coating, the pellets were encapsulated in hard gelatin capsules containing gelatin - 98% and titanium dioxide - 2%, and, in the particular case of implementation, which are ready-made capsules, for example, Capsugel.

The ratio of the weight of the coated pellets to the weight of the capsules is approximately 3.4: 1, respectively.

Thus, the ratio of the mass of the nucleus to the mass of the enteric film coating and to the mass of the capsule is about 3.2: 0.2: 1.0.

Table 5 Ingredient Drug A mg / capsule] Drug B mg / capsule] Drug C mg / capsule] Drug D mg / capsule] Drug E [mg / capsule] Drug F [mg / capsule] Proinsulin C peptide 0.5 1,0 2.0 5,0 10.0 17.5 Hydroxypropyl cellulose - - 100.0 - - 60.0 Polyvinylpyrrolidone - 10.5 - 15,5 - - Hydroxypropyl methylcellulose 150.0 120.0 50,0 100.0 200,0 130.0 Microcrystalline cellulose 171.3 190.3 169.8 201.3 111.8 114.3 Enteric coating 18.2 18.2 18.2 18.2 18.2 18.2 The mass of the contents of the capsule 340.0 340.0 340.0 340.0 340.0 340.0 Continuation of table 5 Ingredient The drug is G mg / capsule] The drug N [mg / capsule] Drug J [mg / capsule] Drug K [mg / capsule] Drug L [mg / capsule] Drug M [mg / capsule] Proinsulin C Peptide 0.5 1,0 2.0 5,0 10.0 17.5 Hydroxypropyl cellulose - - 17,2 - - 10.1 Polyvinylpyrrolidone - 4.2 - 5.3 - - Hydroxypropyl methylcellulose 50,0 - - - 80.0 - Cyclodextrin 1.3 - 2,3 - 7.8 - Lecithin - 2,5 - 5.2 - 8.8 Ethyl cellulose - 16.3 - - 20,4 25.0 Sodium Alginate 5.3 - 10,4 7.9 - - Microcrystalline cellulose 264.7 297.8 289.9 298.4 203.6 260,4 Enteric coating 18.2 18.2 18.2 18.2 18.2 18.2 The mass of the contents of the capsule 340.0 340.0 340.0 340.0 340.0 340.0

Slow Release Release Drugs

For capsules prepared according to Example 3, drug release profiles were determined using a paddle-type dissolution apparatus, and the stirrer was rotated at 50 rpm. The tests were carried out in two stages:

1st stage (acid). Dissolution medium - 0.1 M solution of hydrochloric acid. The volume of the dissolution medium is 900 ml. The test duration is 2 hours.

2nd stage (alkaline). The dissolution medium is a 0.2 M solution of sodium phosphate (Na ₃ PO ₄ · 12H ₂ O) having a pH value of 6.8 ± 0.05. The volume of the dissolution medium is 500 ml. The solution during the experiment was selected for analysis in 15 ml portions after 120, 180, 240, 300, 360, 420, and 480 min from the start of the experiment; after the aliquot was taken, the dissolution medium in the beaker was not replenished. When calculating the amount of C-peptide transferred to the solution, the change in the volume of the dissolution medium was taken into account. The quantification of the C-peptide in the buffer solution was carried out by HPLC. The results are presented in Table 6.

Table 6 Time (min) The amount of C-peptide transferred to the solution,% Drug A Drug C Drug D Drug F Drug G Drug H Drug J Drug L 0 0 0 0 0 0 0 0 0 120 1,5 2.1 2,3 2.1 1.8 1,6 1.9 2.1 180 twenty 21 eighteen fifteen 23 21 22 17 240 fifty 53 43 42 57 60 64 42 300 74 75 68 62 70 80 89 65 360 85 88 76 77 83 91 94 81 420 92 93 88 87 90 94 95 88 480 95 94 92 91 94 94 96 93

The results obtained allow us to argue about the effective stability of the dosage form to the environment of the stomach and the slow release of the C-peptide from the dosage form into the buffer solution (pH 6.8) for 6 hours.

Example 4: Preparation of a solid enteric dosage form of proinsulin C-peptide in the form of capsules with a modified release of the active substance - sustained release (prolonged action), using enteric capsules as a shell

The indicated dosage form of a sustained release (sustained release) proinsulin C-peptide was prepared using a method of applying the active substance to an inert carrier using a fluidized bed apparatus, which includes weighing the ingredients, including the active compound and most excipients, mixing the ingredients of an inert carrier hydroxypropyl methylcellulose and microcrystalline cellulose, directly applying the active substance with the addition of liquid vyazyvayuschego solution onto an inert carrier, drying at a temperature of 30 ° C the obtained pellet coated with the active substance by means of a dryer-granulator "fluidized" bed (mod. V-2.5 Ventilus series). The advantage of this method includes reducing the amount of excipients used, the useful distribution of the active substance on an inert carrier, reducing dust and aerosol contaminants and preventing the separation of components.

Suitable amounts of substances for each batch of capsules are calculated according to the target contents per unit dose, as given in Table 7.

Pellets were encapsulated in hard enteric-soluble capsules of DRCaps containing hydroxypropyl methylcellulose - 93.1%, titanium dioxide - 1.9%, gellan gum - 5.0%, and in the particular case they are ready-made capsules, for example, Capsugel.

The ratio of the weight of the coated pellets to the weight of the capsules is approximately 3.4: 1, respectively.

Table 7 Ingredient Drug A [mg / capsule] Drug B [mg / capsule] Drug C [mg / capsule] Drug D [mg / capsule] Drug E [mg / capsule] Drug F [mg / capsule] Proinsulin C Peptide 0.5 1,0 2.0 5,0 10.0 17.5 Hydroxypropyl cellulose - - 100.0 - - 60.0 Polyvinylpyrrolidone - 10.5 - 15,5 - - Hydroxypropyl methylcellulose 150.0 120.0 50,0 100.0 200,0 130.0

Microcrystalline cellulose 189.5 208.5 188.0 219.5 130.0 132.5 The mass of the contents of the capsule 340.0 340.0 340.0 340.0 340.0 340.0 Continuation of table 7 Ingredient The drug is G mg / capsule] The drug is H mg / capsule] Drug J mg / capsule] Drug K mg / capsule] Drug L [mg / capsule] Drug M [mg / capsule] Proinsulin C Peptide 0.5 1,0 2.0 5,0 10.0 17.5 Hydroxypropyl cellulose - - 17,2 - - 10.1 Polyvinylpyrrolidone - 4.2 - 5.3 - - Hydroxypropyl methylcellulose 50,0 - - - 80.0 - Cyclodextrin 1.3 - 2,3 - 7.8 - Lecithin - 2,5 - 5.2 - 8.8 Ethyl cellulose - 16.3 - - 20,4 25.0 Sodium Alginate 5.3 - 10,4 7.9 - - Microcrystalline cellulose 282.9 316.0 308.1 316.6 221.8 278.6 The mass of the contents of the capsule 340.0 340.0 340.0 340.0 340.0 340.0

Drug release from enteric-coated sustained-release capsules:

For capsules prepared according to Example 4, drug release profiles were determined using a paddle-type dissolution apparatus, stirrer rotation speed of 50 rpm. The tests were carried out in two stages:

1st stage (acid). Dissolution medium - 0.1 M solution of hydrochloric acid. The volume of the dissolution medium is 900 ml. The test duration is 2 hours.

2nd stage (alkaline). The dissolution medium is a 0.2 M solution of sodium phosphate (Na ₃ PO ₄ · 12H ₂ O) having a pH value of 6.8 ± 0.05. The volume of the dissolution medium is 500 ml. The solution during the experiment was selected for analysis in 15 ml portions after 120, 130, 140, 160, 205 and 240 min from the start of the experiment; after the aliquot was taken, the dissolution medium in the beaker was not replenished. When calculating the amount of C-peptide transferred to the solution, the change in the volume of the dissolution medium was taken into account. The quantification of the C-peptide in the buffer solution was carried out by HPLC. The results are presented in Table 8.

Table 8 Time (min) The amount of C-peptide transferred to the solution,% Drug A Drug C Drug D Drug F Drug G The drug N Drug J Drug L 0 0 0 0 0 0 0 0 0 120 0.8 0.9 1D 0.9 0.9 1,2 1,2 1,1 180 twenty 21 eighteen fifteen 23 21 22 17 240 fifty 53 43 42 57 60 64 42 300 74 75 68 62 70 80 89 65 360 85 88 76 77 83 91 94 81 420 92 93 88 87 90 94 95 88 480 95 94 92 91 94 94 96 93

The obtained results allow us to argue about the effective resistance of the dosage form to the stomach environment and the delayed release of the C-peptide from the dosage form into the buffer solution (pH 6.8) over 6 hours.

Example 5: Preparation of a solid enteric-soluble dosage form of a pro-insulin C-peptide with modified release of the active substance in the form of tablets.

These tablets were prepared using the wet granulation method in a fluidized bed apparatus, which includes weighing the ingredients, including the active compound (proinsulin C-peptide) and most excipients, mixing the ingredients, directly granulating with the addition of a liquid binding solution, drying the granules with temperature of 30 ° C, calibration of granules, dusting (for example, talc, magnesium stearate, silicon dioxide colloidal) and pressing the resulting mixture into tablets. The advantage of wet granulation includes improved cohesion and compressibility of the starting components, a useful particle size distribution suitable for pressing, reduction of dust and aerosol contaminants, and prevention of separation of components.

Suitable amounts for each batch of tablets are calculated according to the target contents per unit dose, as given in Table 9.

The granular mixture was compressed into biconvex tablets using a conventional rotary tablet press using a main compression force of about 10 to 20 kN.

The core tablets were coated with an enteric coating containing a methacrylic acid copolymer of 60.80%, talc - 15.20%, titanium dioxide - 12.16%, triethyl citrate - 10.64%, silicon dioxide - 1.20%, and in a particular case which is a ready-made film coating, for example, by Ashland, using a fluidized bed granulator dryer (mod. V-2.5 of the Ventilus series). Before coating, tablets were dust-free and weighed. Enteric coating of the tablets was carried out until the weight gain of the tablets was approximately 6%.

Table 9 Ingredient Drug A [mg / tablet] Drug B [mg / tablet] Drug C [mg / tablet] Drug D [mg / tablet] Drug E [mg / tablet] The drug is F "mg / tablet Proinsulin C Peptide 0.5 0.5 1,0 2.0 2.0 4.0 Hydroxypropyl cellulose - - 3.2 - - 4.8 Polyvinylpyrrolidone - 0.8 - 4.0 - - Hydroxypropyl methylcellulose 1,6 - - - 7.2 - Microcrystalline cellulose 77.1 78.3 72,2 73,2 66.6 69.6 Silicon dioxide 0.8 - 3.2 - 4.0 - Magnesium stearate 0.8 - 0.4 - 0.2 - Talc - 0.4 - 0.8 - 1,6 Tablet core mass 80 80 80 80 80 80 Enteric coating 5 5 5 5 5 5 Tablet weight 85 85 85 85 85 85

Continuation of table 9 Ingredient Drug G [mg / tablet] The drug is H mg / tablet] Drug J [mg / tablet] Drug K [mg / tablet] Drug L [mg / tablet] Drug M [mg / tablet] Proinsulin C Peptide 0.5 1,0 2.0 2.0 4.0 4.0 Hydroxypropyl cellulose - - 3.2 - - 4.8 Polyvinylpyrrolidone - 0.8 - 4.0 - - Hydroxypropyl methylcellulose 1,6 - - - 7.2 - Mannitol - - 30,0 40,0 - 50,0 Sorbitol 30,0 50,0 - - 50,0 - Cyclodextrin 1.3 - 5.2 - 10,4 - Lecithin - 2.6 - 4.0 - 12.0 Microcrystalline cellulose 45.0 25,2 36.0 29.2 8.2 7.6 Silicon dioxide 0.8 - 3.2 - 4.0 - Magnesium stearate 0.8 - 0.4 - 0.2 - Talc - 0.4 - 0.8 - 1,6 Tablet core mass 80 80 80 80 80 80 Enteric coating 5 5 5 5 5 5 Tablet weight 85 85 85 85 85 85

Drug Release from Modified Release Tablets:

For the tablets obtained according to Example 5, drug release profiles were determined using a paddle-type dissolution device, the stirrer speed was 50 rpm. The tests were carried out in two stages:

1st stage (acid). Dissolution medium - 0.1 M solution of hydrochloric acid. The volume of the dissolution medium is 900 ml. The test duration is 2 hours.

2nd stage (alkaline). The dissolution medium is a 0.2 M solution of sodium phosphate (Na ₃ PO ₄ · 12H ₂ O) having a pH value of 6.8 ± 0.05. The volume of the dissolution medium is 500 ml. The solution during the experiment was selected for analysis in 15 ml portions after 120, 130, 140, 160, 205 and 240 min from the start of the experiment; after the aliquot was taken, the dissolution medium in the beaker was not replenished. When calculating the amount of C-peptide transferred to the solution, the change in the volume of the dissolution medium was taken into account. The quantification of the C-peptide in the buffer solution was carried out by HPLC. The results are presented in Table 10.

Table 10 Time (min) The amount of C-peptide transferred to the solution,% Drug A Drug C Drug D Drug F Drug G Drug H Drug J Drug L 0 0 0 0 0 0 0 0 0 120 1.3 2.0 2,3 2.1 1.4 1,2 1,5 1,1 130 2 2.9 2,5 2.7 1.8 1.9 2.2 1.8 140 72 75 70 76 68 65 63 56 160 86 84 80 84 85 83 87 79 205 91 90 89 90 93 92 93 91 240 92 91 91 93 95 93 96 94

The results obtained suggest the effective resistance of the dosage form to the environment of the stomach and the rapid (immediate) release of the C-peptide from the dosage form into a buffer solution (pH 6.8), which simulates the intestinal environment.

Thus, the developed dosage form eliminates the destruction of the C-peptide in the acidic environment of the stomach and under the action of proteolytic enzymes in it.

Example 6: Obtaining a solid enteric dosage form of a modified-release proinsulin C peptide in the form of tablets in the form of sustained release tablets of a proinsulin C peptide

The process of preparing a solid enteric-soluble dosage form of a pro-insulin C-peptide with modified release of the active substance in the form of tablets with prolonged release of a prolonged-release pro-insulin C-peptide (sustained release) using a fluidized bed apparatus includes the steps of wet granulating the mass of pro-insulin C-peptide with auxiliary ingredients with a binder solution (e.g. cellulose derivative or polyvinylpyrrolidone ), drying the granules at a temperature of 35 ° C, almost immediately after that - applying to the granules a polymer (for example, ethyl cellulose or sodium alginate) with controlled permeability for the C-peptide, until a sufficient amount of polymer is applied to create the desired speed or sustained release patterns. Dusting (for example, talc, magnesium stearate, colloidal silicon dioxide) and compressing the resulting mixture into tablets.

Suitable amounts for each batch of tablets were calculated according to the target contents per unit dose, as given in Table 11.

The granular mixture was compressed into biconvex tablets using a conventional rotary tablet press using a main compression force of about 10 to 20 kN.

The core tablets were coated with an enteric coating containing a methacrylic acid copolymer of 60.80%, talc - 15.20%, titanium dioxide - 12.16%, triethyl citrate - 10.64%, silicon dioxide - 1.20%, and in a particular case which is a ready-made film coating, for example, by Ashland, using a fluidized bed granulator dryer (mod. V-2.5 of the Ventilus series). Before coating, tablets were dust-free and weighed. Enteric coating of the tablets was carried out until the weight gain of the tablets was approximately 6%.

Table 11 Ingredient Drug N [mg / tablet] Drug O [mg / tablet] Drug P [mg / tablet] Drug Q [mg / tablet] Proinsulin C Peptide 2.0 2.0 4.0 4.0 Hydroxypropyl cellulose 3.2 - - 4.8 Polyvinylpyrrolidone - 4.0 - - Hydroxypropyl methylcellulose - - 7.2 - Mannitol 30,0 - - 40,0 Sorbitol - 30,0 40,0 - Cyclodextrin 5.2 - 10,4 - Lecithin - 4.0 - 12.0 Microcrystalline cellulose 32,0 49.2 7.2 10.6

Ethyl cellulose - 4.0 - 7.0 Sodium Alginate 4.0 - 7.0 - Silicon dioxide 3.2 - 4.0 - Magnesium stearate 0.4 - 0.2 - Talc - 0.8 - 1,6 Tablet core mass 80 80 80 80 Enteric coating 5 5 5 5 Tablet weight 85 85 85 85

Example 7: Preparation of a solid enteric dosage form of proinsulin C-peptide in the form of sustained release C-peptide tablets

The process of preparing sustained-release (sustained release) C-peptide dosage forms using a fluidized bed apparatus includes the steps of wet granulating a mass of C-peptide with auxiliary ingredients using a binder solution (as in Example 6), followed by mixing with the ingredient for example, hydroxypropyl methylcellulose, regulating the release of the C-peptide from the dosage form, drying the granules at a temperature of 35 ° C. Dusting (for example, talc, magnesium stearate, colloidal silicon dioxide) and compressing the resulting mixture into tablets.

Suitable amounts for each batch of tablets were calculated according to the target contents per unit dose, as shown in Table 12.

The granular mixture was compressed into biconvex tablets using a conventional rotary tablet press using a main compression force of about 10 to 20 kN.

The core tablets were coated with an enteric coating containing a methacrylic acid copolymer of 60.80%, talc - 15.20%, titanium dioxide - 12.16%, triethyl citrate - 10.64%, silicon dioxide - 1.20%, and, in a special case, which is a finished film coating, for example, Ashland company, using a fluidized bed granulator dryer (mod. V-2.5 of the Ventilus series). Before coating, tablets were dust-free and weighed. Enteric coating of the tablets was carried out until the weight gain of the tablets was approximately 6%.

Table 12 Ingredient Drug R [mg / tablet] Drug S [mg / tablet] Drug T [mg / tablet] Drug U [mg / tablet] Proinsulin C Peptide 2.0 2.0 4.0 4.0 Hydroxypropyl cellulose 3.2 - 4.8 - Polyvinylpyrrolidone - 1,6 - 4.0 Hydroxypropyl methylcellulose 40,0 48.0 40,0 56.0 Microcrystalline cellulose 33,2 28.0 27.6 15,2 silicon dioxide 0.8 - 3.2 - Magnesium stearate 0.8 - 0.4 - Talc - 0.4 - 0.8 Tablet core mass 80 80 80 80 Enteric coating 5 5 5 5 Tablet weight 85 85 85 85

Drug release from sustained release tablets:

For tablets prepared according to Examples 6, 7, drug release profiles were determined using a paddle-type dissolution apparatus, and the stirrer was rotated at 50 rpm. The tests were carried out in two stages:

1st stage (acid). Dissolution medium - 0.1 M solution of hydrochloric acid. The volume of the dissolution medium is 900 ml. The test duration is 2 hours.

2nd stage (alkaline). The dissolution medium is a 0.2 M solution of sodium phosphate (Na ₃ PO ₄ · 12H ₂ O) having a pH value of 6.8 ± 0.05. The volume of the dissolution medium is 500 ml. The solution during the experiment was selected for analysis in 15 ml portions after 120, 180, 240, 300, 360, 420, and 480 min from the start of the experiment; after the aliquot was taken, the dissolution medium in the beaker was not replenished. When calculating the amount of C-peptide transferred to the solution, the change in the volume of the dissolution medium was taken into account. Quantification of the C-peptide in the buffer solution was carried out by HPLC. The results are presented in Table 13.

Table 13 Time
(min) The amount of C-peptide transferred to the solution,% Drug N Drug O Drug P Drug Q Drug R Drug S Drug T Drug U 0 0 0 0 0 0 0 0 0 120 1.3 2 2,3 2.1 1.4 1,2 1,5 1,1 180 25 twenty eighteen fifteen 25 twenty 25 19 240 60 53 43 42 67 60 67 42 300 85 75 63 62 89 80 89 65 360 93 88 79 77 93 91 94 81 420 95 93 88 87 95 93 95 88 480 96 94 92 91 96 93 96 93

The obtained results allow us to argue about the effective resistance of the dosage form to the environment of the stomach and about the controlled release of the C-peptide from the dosage form into the buffer solution (pH 6.8) for 6 hours.

The content of proinsulin C-peptide in tablet and capsule dosage forms of the C-peptide was checked during storage. The results are presented in tables 14 and 15.

As can be seen from these tables, the content of the C-peptide remains practically stable for at least 12 months of storage of the claimed forms at temperatures up to + 8 ° C.

Thus, the examples of specific performance confirm the receipt of solid dosage forms of the C-peptide that meet all the requirements of GP XI. In addition, the proposed solid dosage forms of proinsulin C-peptide provide immediate or delayed release (prolonged action) of the active substance, as well as the possibility of long-term preservation in a domestic refrigerator, which is especially important for consumers - individuals.

Table 14 Data on the stability of encapsulated dosage forms of the C-peptide during storage
Storage conditions: temperature 2-8 ° C, relative humidity 40-60% Example number, product name At the time of manufacture After 6 months After 12 months The content of C-peptide in one capsule, mg Foreign matter The content of C-peptide in one capsule, mg Foreign matter The content of C-peptide in one capsule, mg Foreign matter one 2 3 four 5 6 7 Example 1, drug A 0.503 ± 0.023 Single impurity - (2.2 ± 0.1)%; Total impurities - (3.7 ± 0.2)% 0.501 ± 0.023 Single impurity - (2.2 ± 0.1)%; Total impurities - (3.7 ± 0.2)% 0.502 ± 0.020 Single impurity - (2.3 ± 0.1)%; Total impurities - (3.7 ± 0.2)% Example 1, drug D 1,983 ± 0,019 Single impurity - (2.2 ± 0.1)%; Total impurities - (3.7 ± 0.2)% 1.993 ± 0.019 Single impurity - (2.6 ± 0.13)%; Total impurities - (4.0 ± 0.2)% 1.981 ± 0.021 Single admixture - (2.6 ± 0.13)%; Total impurities - (4.1 ± 0.2)% Example 1, drug J 0.983 ± 0.020 Single impurity - (2.2 ± 0.1)%; Total impurities - (3.7 ± 0.2)% 0.986 ± 0.020 Single impurity - (2.2 ± 0.1)%; Total impurities - (3.7 ± 0.2)% 0.985 ± 0.019 Single impurity - (2.2 ± 0.1)%; Total impurities - (3.8 ± 0.2)% Example 1, drug L 2.953 ± 0.021 Single impurity - (2.2 ± 0.1)%; Total impurities - (3.7 ± 0.2)% 2.943 ± 0.021 Single impurity - (2.4 ± 0.1)%; Total impurities - (3.8 ± 0.2)% 2.94b ± 0.019 Single admixture - (2.4 ± 0.1)%; Total impurities - (3.9 ± 0.2)% Example 2, drug A 0.503 ± 0.023 Single impurity - (2.2 ± 0.1)%; Total impurities - (3.7 ± 0.2)% 0.510 ± 0.019 Single admixture - (2.3 ± 0.1)%; Total impurities - (3.6 ± 0.2)% 0.501 ± 0.025 Single impurity - (2.5 ± 0.1)%; Total impurities - (3.7 ± 0.2)% Example 2, drug D 1,983 ± 0,019 Single impurity - (2.6 ± 0.13)%; Total impurities - (4.0 ± 0.2)% 1,990 ± 0,019 Single impurity - (2.7 ± 0.13)% Total impurities - (4.0 ± 0.2)% 1,978 ± 0,022 Single admixture - (2.6 ± 0.13)%; Total impurities - (4.1 ± 0.2)%

Continuation of table 14 one 2 3 four 5 6 7 Example 2, drug J 1.013 ± 0.020 Single impurity - (2.2 ± 0.1)%; Total impurities - (3.7 ± 0.2)% 1.009 ± 0.024 Single impurity - (2.3 ± 0.1)%; Total impurities - (3.7 ± 0.2)% 0.993 ± 0.020 Single admixture - (2.4 ± 0.1)%; Total impurities - (3.9 ± 0.2)% Example 2, drug M 4.953 ± 0.021 Single impurity - (2.4 ± 0.1)%; Total impurities - (3.8 ± 0.2)% 4.967 ± 0.018 Single impurity - (2.3 ± 0.1)%; Total impurities - (3.8 ± 0.2)% 4,950 ± 0,018 Single admixture - (2.5 ± 0.1)%; Total impurities - (4.0 ± 0.2)% Example 4, drug A 0.509 ± 0.023 Single impurity - (2.0 ± 0.1)%; Total impurities - (3.4 ± 0.2)% 0.507 ± 0.020 Single impurity - (2.2 ± 0.1)%; Total impurities - (3.8 ± 0.2)% 0.497 ± 0.025 Single admixture - (2.5 ± 0.1)%; Total impurities - (4.0 ± 0.2)% Example 4, drug D 5.012 ± 0.019 Single impurity - (2.3 ± 0.1)%; Total impurities - (3.8 ± 0.2)% 5.002 ± 0.021 Single admixture - (2.3 ± 0.1)%; Total impurities - (3.9 ± 0.2)% 4.991 ± 0.020 Single admixture - (2.5 ± 0.1)%; Total impurities - (4.1 ± 0.2)% Example 4, drug F 17,503 ± 0,020 Single impurity - (2.6 ± 0.13)%; Total impurities - (4.0 ± 0.2)% 17.495 ± 0.020 A single impurity - (2.5 ± 0.13)% The amount of impurities - (4.1 ± 0.2)% 17.487 ± 0.025 A single impurity - (2.9 ± 0.13)%; The amount of impurities - (4.3 ± 0.2)% Example 4, drug H 1.009 ± 0.021 Single impurity - (2.2 ± 0.1)%; Total impurities - (3.7 ± 0.2)% 0.994 ± 0.021 Single impurity - (2.1 ± 0.1)%; Total impurities - (3.6 ± 0.2)% 0.996 ± 0.021 Single admixture - (2.3 ± 0.1)%; Total impurities - (3.9 ± 0.2)% Example 4, drug L 10,003 ± 0,023 Single admixture - (2.5 ± 0.1)%; Total impurities - (4.0 ± 0.2)% 9.992 ± 0.021 Single impurity - (2.5 ± 0.1)%; Total impurities - (3.9 ± 0.2)% 9.988 ± 0.023 Single admixture - (2.6 ± 0.1)%; Total impurities - (4.2 ± 0.2)%

Table 15 Data on the stability of the tablet dosage forms of the C-peptide during storage
Storage conditions: temperature 2-8 ° C, relative humidity 40-60% Example number, product name At the time of manufacture After 6 months After 12 months The content of C-peptide in one capsule, mg Foreign matter The content of C-peptide in one capsule, mg Foreign matter The content of C-peptide in one capsule, mg Foreign matter one 2 3 four 5 6 7 Example 5, drug C 1.103 ± 0.023 Single impurity - (2.2 ± 0.1)%; Total impurities - (3.7 ± 0.2)% 1,093 ± 0,021 Single admixture - (2.4 ± 0.1)%; Total impurities - (3.9 ± 0.2)% 1,089 ± 0,021 Single admixture - (2.6 ± 0.1)%; Total impurities - (4.2 ± 0.2)% Example 5, drug E 1,983 ± 0,019 Single impurity - (2.2 ± 0.1)%; Total impurities - (3.7 ± 0.2)% 1,991 ± 0,022 Single admixture - (2.6 ± 0.13)%; Total impurities - (4.1 ± 0.2)% 1,984 ± 0,018 Single admixture - (2.7 ± 0.13)%; Total impurities - (4.4 ± 0.2)% Example 5, drug G 0.503 ± 0.020 Single impurity - (2.2 ± 0.1)%; Total impurities - (3.7 ± 0.2)% 0.500 ± 0.019 Single admixture - (2.3 ± 0.1)%; Total impurities - (3.9 ± 0.2)% 0.498 ± 0.021 Single admixture - (2.6 ± 0.1)%; Total impurities - (4.3 ± 0.2)% Example 5, drug K 1,997 ± 0,021 Single impurity - (2.2 ± 0.1)%; Total impurities - (3.7 ± 0.2)% 1.989 ± 0.023 Single admixture - (2.4 ± 0.1)%; Total impurities - (3.9 ± 0.2)% 1.977 ± 0.021 Single admixture - (2.6 ± 0.1)%; Total impurities - (4.2 ± 0.2)% Example 5, drug L 4.089 ± 0.019 Single impurity - (2.2 ± 0.1)%; Total impurities - (3.7 ± 0.2)% 4.088 ± 0.021 Single impurity - (2.1 ± 0.1)%; Total impurities - (3.8 ± 0.2)% 4.079 ± 0.019 Single admixture - (2.5 ± 0.1)%; Total impurities - (4.1 ± 0.2)% Example 6, drug N 2.014 ± 0.022 Single impurity - (2.6 ± 0.13)%; Total impurities - (4.0 ± 0.2)% 2.006 ± 0.022 Single admixture - (2.7 ± 0.13)%; Total impurities - (4.1 ± 0.2)% 1.989 ± 0.024 A single impurity - (2.9 ± 0.13)% The amount of impurities - (4.4 ± 0.2)%

Continuation of table 15 one 2 3 four 5 6 7 Example 6, drug Q 4.013 ± 0.020 Single impurity - (2.2 ± 0.1)%; Total impurities - (3.7 ± 0.2)% 4.015 ± 0.020 Single admixture - (2.3 ± 0.1)%; Total impurities - (3.9 ± 0.2)% 3.998 ± 0.019 Single impurity - (2.5 ± 0.1)%; Total impurities - (3.9 ± 0.2)% Example 7, drug R 2.015 ± 0.021 Single impurity - (2.4 ± 0.1)%; Total impurities - (3.8 ± 0.2)% 2.018 ± 0.021 Single admixture - (2.3 ± 0.1)%; Total impurities - (3.9 ± 0.2)% 2,009 ± 0,020 Single admixture - (2.7 ± 0.1)%; Total impurities - (4.3 ± 0.2)% Example 7, drug U 4,093 ± 0,023 Single impurity - (2.4 ± 0.1)%; Total impurities - (3.8 ± 0.2)% 4.098 ± 0.023 Single admixture - (2.5 ± 0.1)%; Total impurities - (4.0 ± 0.2)% 4.079 ± 0.025 Single impurity - (2.9 ± 0.1)%; Total impurities - (4.4 ± 0.2)%

Claims (24)

1. A solid enteric dosage form of proinsulin C-peptide for oral administration, consisting of a core comprising proinsulin C-peptide and excipient as an active substance and a coating coating thereof, characterized in that the dosage form is tablets, the core of which is as excipients contains microcrystalline cellulose, polyvinylpyrrolidone or hydroxypropyl cellulose or hydroxypropyl methyl cellulose, magnesium stearate, colloidal silicon dioxide and talc, in the following ratio Components, wt.%:
Proinsulin C peptide - 0.01-5.0
hydroxypropyl cellulose - 1.0-6.0
or hydroxypropyl methylcellulose - 1.0-10.0
or polyvinylpyrrolidone - 1.0-5.0
magnesium stearate - 0.01-1.0
silicon dioxide colloidal - 0.01-10.0
talc - 0.01-3.0
microcrystalline cellulose - up to 100,
and the shell is an enteric film coating containing a copolymer of methacrylic and acrylic acids, talc, titanium dioxide, triethyl citrate, silicon dioxide, in the following ratio, wt.%
talc - 10.0-20.0
titanium dioxide - 5.0-15.0
triethyl citrate - 7.0-14.0
silicon dioxide - 0.2-2.2
copolymer of methacrylic and acrylic acids - up to 100. 2. The solid enteric dosage form of proinsulin C-peptide according to claim 1, characterized in that the core as excipients additionally contains at least one component selected from the group of mannitol or sorbitol, cyclodextrin or lecithin, in the following ratio, wt.% :
Proinsulin C peptide - 0.01-5.0
hydroxypropyl cellulose - 1.0-6.0
or hydroxypropyl methylcellulose - 1.0-10.0
or polyvinylpyrrolidone - 1.0-5.0
mannitol - 1-90.0
or sorbitol - 1-90.0
cyclodextrin - 0.03-15.0
or lecithin - 0.03-15.0
magnesium stearate - 0.01-1.0
silicon dioxide colloidal - 0.01-10.0
talc - 0.01-3.0
microcrystalline cellulose - up to 100 3. A solid enteric dosage form of proinsulin C-peptide for oral administration, consisting of a core comprising proinsulin C-peptide and an excipient and a coating coating thereof, characterized in that they are sustained release tablets, the core of which contains microcrystalline cellulose as excipients, polyvinylpyrrolidone or hydroxypropyl cellulose or hydroxypropyl methyl cellulose, magnesium stearate, colloidal silicon dioxide and talc, in the following ratio, wt.%:
Proinsulin C peptide - 0.01-5.0
hydroxypropyl methylcellulose - 1.0-80.0
or hydroxypropyl cellulose - 1.0-35.0
or polyvinylpyrrolidone - 1.0-5.0
magnesium stearate - 0.01-1.0
silicon dioxide colloidal - 0.01-10.0
talc - 0.01-3.0
microcrystalline cellulose - up to 100,
and the shell is an enteric film coating containing a copolymer of methacrylic and acrylic acids, talc, titanium dioxide, triethyl citrate, silicon dioxide, in the following ratio, wt.%:
talc - 10.0-20.0
titanium dioxide - 5.0-15.0
triethyl citrate - 7.0-14.0
silicon dioxide - 0.2-2.2
copolymer of methacrylic and acrylic acids - up to 100 4. The solid enteric dosage form of proinsulin C-peptide according to claim 3, characterized in that the core as excipients further comprises at least one component selected from the group consisting of mannitol or sorbitol, cyclodextrin or lecithin, ethyl cellulose or sodium alginate , in the following ratio of components, wt.%:
Proinsulin C peptide - 0.01-5.0
hydroxypropyl cellulose - 1.0-35.0
or hydroxypropyl methylcellulose - 1.0-80.0
or polyvinylpyrrolidone - 1.0-5.0
mannitol - 1.0-90.0
or sorbitol - 1.0-90.0
cyclodextrin - 0.03-15.0
or lecithin - 0.03-15.0
ethyl cellulose - 1.0-20.0
or sodium alginate - 0.1-10.0
magnesium stearate - 0.1-1.0
silicon dioxide colloidal - 0.1-10.0
talc - 0.1-3.0
microcrystalline cellulose - up to 100 5. A solid enteric dosage form of proinsulin C-peptide for oral administration, consisting of a core comprising proinsulin C-peptide and an excipient, and a coating coating thereof, characterized in that the dosage form is a capsule, the core of which contains microcrystalline cellulose as excipients, polyvinylpyrrolidone or hydroxypropyl cellulose, or hydroxypropyl methyl cellulose, in the following ratio, wt.%:
Proinsulin C peptide - 0.01-5.0
hydroxypropyl cellulose - 1.0-10.0
or hydroxypropyl methylcellulose - 1.0-10.0
or polyvinylpyrrolidone - 1.0-5.0
microcrystalline cellulose - up to 100,
the shell consists of an enteric film coating and a hard capsule, the enteric film coating containing a copolymer of methacrylic and acrylic acids, talc, titanium dioxide, triethyl citrate, silicon dioxide, in the following ratio, wt.%:
talc - 10.0-20.0
titanium dioxide - 5.0-15.0
triethyl citrate - 7.0-14.0
silicon dioxide - 0.2-2.2
copolymer of methacrylic and acrylic acids - up to 100,
and the hard capsule contains gelatin and titanium dioxide in the following ratio, wt.%:
titanium dioxide - 0.1-5.0
gelatin - up to 100 6. The solid enteric dosage form of proinsulin C-peptide according to claim 5, characterized in that the core additionally contains cyclodextrin or lecithin as excipients, in the following ratio, wt.%:
Proinsulin C peptide - 0.01-5.0
hydroxypropyl cellulose - 1.0-10.0
or hydroxypropyl methylcellulose - 1.0-10.0
or polyvinylpyrrolidone - 1.0-5.0
cyclodextrin - 0.03-15.0
or lecithin - 0.03-15.0
microcrystalline cellulose - up to 100 7. A solid enteric dosage form of proinsulin C-peptide for oral administration, consisting of a core comprising proinsulin C-peptide and an excipient and its coating, characterized in that it is a prolonged-action capsule, the core of which contains microcrystalline cellulose as excipients, polyvinylpyrrolidone or hydroxypropyl cellulose, or hydroxypropyl methyl cellulose, in the following ratio, wt.%:
Proinsulin C peptide - 0.01-5.0
hydroxypropyl methylcellulose - 1.0-80.0
or hydroxypropyl cellulose - 1.0-35.0
or polyvinylpyrrolidone - 1.0-5.0
microcrystalline cellulose - up to 100,
the shell consists of an enteric film coating and a hard capsule, the enteric film coating containing a copolymer of methacrylic and acrylic acids, talc, titanium dioxide, triethyl citrate, silicon dioxide, in the following ratio, wt.%:
talc - 10.0-20.0
titanium dioxide - 5.0-15.0
triethyl citrate - 7.0-14.0
silicon dioxide - 0.2-2.2
copolymer of methacrylic and acrylic acids - up to 100,
and the hard capsule contains gelatin and titanium dioxide in the following ratio, wt.%:
titanium dioxide - 0.1-5.0
gelatin - up to 100 8. The solid enteric dosage form of proinsulin C-peptide according to claim 7, characterized in that the core as excipients additionally contains at least one component selected from the group comprising cyclodextrin or lecithin, ethyl cellulose or sodium alginate, in the following ratio components, wt.%:
Proinsulin C peptide - 0.01-5.0
hydroxypropyl cellulose - 1.0-35.0
or hydroxypropyl methylcellulose - 1.0-80.0
or polyvinylpyrrolidone - 1.0-5.0
cyclodextrin - 0.03-15.0
or lecithin - 0.03-15.0
ethyl cellulose - 1.0-20.0
or sodium alginate - 0.1-10.0
microcrystalline cellulose - up to 100 9. A solid enteric dosage form of proinsulin C-peptide for oral administration, consisting of a core comprising proinsulin C-peptide and excipient as an active substance and its coating, characterized in that the dosage form is a capsule whose core as excipients contains microcrystalline cellulose, polyvinylpyrrolidone or hydroxypropyl cellulose, or hydroxypropyl methyl cellulose, in the following ratio, wt.%:
Proinsulin C peptide - 0.01-5.0
hydroxypropyl cellulose - 1.0-10.0
or hydroxypropyl methylcellulose - 1.0-10.0
or polyvinylpyrrolidone - 1.0-5.0
microcrystalline cellulose - up to 100,
and the shell is a solid enteric capsule containing gelatin, titanium dioxide, gellan gum and hydroxypropyl cellulose in the following ratio, wt.%:
titanium dioxide - 1.0-2.0
gellan gum - 1.0-5.0
hydroxypropyl methylcellulose - up to 100 10. The solid enteric dosage form of proinsulin C-peptide according to claim 9, characterized in that the core as excipients further comprises cyclodextrin or lecithin, in the following ratio, wt.%:
Proinsulin C peptide - 0.01-5.0
hydroxypropyl cellulose - 1.0-10.0
or hydroxypropyl methylcellulose - 1.0-10.0
or polyvinylpyrrolidone - 1.0-5.0
cyclodextrin - 0.03-15.0
or lecithin - 0.03-15.0
microcrystalline cellulose - up to 100 11. A solid enteric dosage form of proinsulin C-peptide for oral administration, consisting of a core comprising proinsulin C-peptide and excipient as an active substance and its coating, characterized in that it is a prolonged-action capsule, the core of which is as excipients contains microcrystalline cellulose, polyvinylpyrrolidone or hydroxypropyl cellulose, or hydroxypropyl methyl cellulose, in the following ratio, wt.%:
Proinsulin C peptide - 0.01-5.00
hydroxypropyl methylcellulose - 1.0-80.0
or hydroxypropyl cellulose - 1.0-35.0
or polyvinylpyrrolidone - 1.0-5.0
microcrystalline cellulose - up to 100,
and the shell is a solid enteric capsule containing gelatin, titanium dioxide, gellan gum and hydroxypropyl cellulose in the following ratio, wt.%:
titanium dioxide - 1.0-2.0
gellan gum - 1.0-5.0
hydroxypropyl methylcellulose - up to 100 12. The solid enteric dosage form of proinsulin C-peptide according to claim 11, characterized in that the core as excipients additionally contains at least one component selected from the group comprising cyclodextrin or lecithin, ethyl cellulose or sodium alginate, in the following ratio components, wt.%:
Proinsulin C peptide - 0.01-5.0
hydroxypropyl cellulose - 1.0-35.0
or hydroxypropyl methylcellulose - 1.0-80.0
or polyvinylpyrrolidone - 1.0-5.0
cyclodextrin - 0.03-15.0
or lecithin - 0.03-15.0
ethyl cellulose - 1.0-20.0
or sodium alginate - 0.1-10.0
microcrystalline cellulose - up to 100 13. A method of preparing a solid enteric dosage form of proinsulin C-peptide for oral administration in the form of tablets according to any one of claims 1 to 4, which comprises mixing an aqueous solution of proinsulin C-peptide with a carrier - at least microcrystalline cellulose, the resulting mixture moisten with an aqueous solution of hydroxypropyl cellulose or hydroxypropyl methyl cellulose or polyvinyl pyrrolidone, form granules that are dried at a temperature not exceeding 35 ° C, calibrated and dusted with talc, magnesium stearate and cre colloidal dioxide, then kernels are formed from dried granules in the form of tablets, which are dedusted and enteric coated with an enteric coating film, by spraying an aqueous suspension containing a copolymer of methacrylic and acrylic acids, talc, titanium dioxide, triethyl citrate and silicon dioxide to increase the weight of the tablets by 4-10%. 14. The method according to item 13, wherein the aqueous solution of proinsulin C-peptide is pre-mixed with an aqueous solution of cyclodextrin or lecithin, and mannitol or sorbitol is additionally added as a carrier. 15. The method according to item 13, wherein the carrier is additionally added hydroxypropylmethyl cellulose. 16. The method according to item 13, wherein the aqueous solution of proinsulin C-peptide is pre-mixed with an aqueous solution of cyclodextrin or lecithin, and an aqueous solution of sodium alginate or ethyl cellulose is additionally applied to the dried granules before applying the enteric film coating. 17. A method of obtaining a solid enteric dosage form of proinsulin C peptide for oral administration in capsule form according to any one of claims 5 to 8, wherein the aqueous solution of proinsulin C peptide is mixed with an aqueous solution of hydroxypropyl cellulose or hydroxypropyl methyl cellulose or polyvinylpyrrolidone obtained the solution is sprayed onto a carrier — at least microcrystalline cellulose — and pellets are formed in the form of pellets, which are dried at a temperature not exceeding 35 ° C, then on nanopellet cores they enter an enteric film coating by spraying an aqueous suspension containing a copolymer of methacrylic and acrylic acids, talc, titanium dioxide, triethyl citrate, silicon dioxide, to increase the pellet mass by 4-10%, and then enter the pellets coated with an enteric film coating in gelatin capsules and titanium dioxide. 18. The method according to 17, characterized in that cyclodextrin or lecithin is additionally added to the aqueous solution of the proinsulin C-peptide. 19. The method according to 17, characterized in that the carrier is additionally added hydroxypropylmethyl cellulose. 20. The method according to 17, characterized in that cyclodextrin or lecithin is additionally added to the aqueous solution of proinsulin C-peptide, hydroxypropyl methyl cellulose is additionally added as a carrier, and an aqueous solution of sodium alginate or ethyl cellulose is additionally applied to the dried pellets before coating with an enteric film coating . 21. A method for preparing a solid enteric dosage form of proinsulin C peptide for oral administration in capsule form according to any one of claims 9-12, wherein the aqueous solution of proinsulin C peptide is mixed with an aqueous solution of hydroxypropyl cellulose or hydroxypropyl methyl cellulose or polyvinylpyrrolidone obtained the mixture is applied by spraying on a carrier - at least microcrystalline cellulose, and form pellet kernels that are dried at a temperature not exceeding 35 ° C and then encapsulated in a capsule Materials containing titanium dioxide, gellan gum and hydroxypropyl methylcellulose. 22. The method according to item 21, characterized in that the cyclic dextrin or lecithin is additionally added to the aqueous solution of the proinsulin C-peptide. 23. The method according to item 21, wherein the carrier is additionally added hydroxypropylmethyl cellulose. 24. The method according to p. 21, characterized in that cyclodextrin or lecithin is additionally added to the aqueous solution of proinsulin C-peptide, hydroxypropyl methylcellulose is additionally added as a carrier, and an aqueous solution of sodium alginate or ethyl cellulose is additionally applied to the dried pellets before encapsulation.