Gastral retentive compositions and its production methods

FIELD: food industry.

SUBSTANCE: present invention relates to gastral retentive composition containing active agent granulated together with the mixture of the first and the second gelatinating agents and mentioned composition production method the first gelatinating agent is a mixture of microcrystalline cellulose and sodium-carboxymethyl cellulose the second gelatinating agent is a compound with viscosity of 1% water solution which makes at least 600 centipoise at 25°C active agent is chosen from antibacterial compounds such as fluoroquinolones, antidiabetic compounds and antihypertensive medicinal agents.

EFFECT: invention provides gastral retentive composition with sustained release effect, which stays in stomach; medical agent has maximal absorption with improved therapeutic action there.

24 cl, 2 ex

 

The invention relates to gastroretentive compositions, particularly tablets and method of manufacture of such compositions.

An important factor affecting the absorption of drugs in the gastrointestinal tract, taken orally by the way, is the time in the gastro-kishechnom tract.

It is known that some active substances, such as Metformin and ciprofloxacin, are absorbed only in the area from the stomach to the small intestine, i.e. in the upper part of the gastrointestinal tract.

Therefore, in order to achieve maximum effectiveness with minimum number of active substances, it would be useful if the composition is retained in the stomach for a long time and provided there is a possibility of delayed release of the active substance.

To obtain compositions with such a slow release in the stomach, had already made some attempts based on the use of multilayer tablets, such as tablets in patent US 6, 797, 283 (Edgren et al.) and patent application US patent application 20030232081, or on the use of tablets, which are small enough to be swallowed, and which swell after ingestion, as, for example, in patent US 6, 635, 280 (Shell et al.) and US 6, 660, 300 (Timmins et al.).

However, these compositions cannot be considered fully satisfactory, and still being the t need for compositions, who are able to stay in the upper gastrointestinal kishechnogo tract and release of the active substance in the stomach for several hours.

Unexpectedly and surprisingly, the inventors have found that these objectives can be fully achieved by using gastroretentive compositions comprising the active substance, granulated together with a mixture of weak gelling agents, strong heliopause means and means forming a gas.

In the present invention "weak gelling agent" is a compound having a viscosity of less than 175 centipoises if it is in the form of 2.6% (wt./about) water dispersion at 25°C.

"Strong gelling agent" is a compound having a viscosity of at least 600 centipoises if it is in the form of a 1% (wt./about) aqueous solution at 25°C.

Without intending to be bound by a particular mechanism, suppose that the weak gelling the tool helps the matrix faster to swell because of its ability to rapid hydration, and effervescent agent, which releases the gas in the reaction environment of the stomach, helps to keep the tablet in the stomach in a floating state. Use a strong gel-forming means provides stability of the swollen matrix tablets and helps zadereev shall be allocated to the gas in the matrix tablets.

In other words, as the acidic contents of the stomach enters the core of the gel matrix, it responds with a tool that emit gas for the evolution of gas. The emitted gas is enclosed in a gel-like matrix and slowly released to the surface of the gel matrix, as the drug diffuses or is released from the gel matrix. The released gas is adsorbed on the surface of the gel matrix, forming a layer of bubbles on the surface, and helps to control the dissolution or leaching of drug from the matrix. The composition is retained in the stomach for a long time, releasing in the stomach almost all inside the drug for further absorption.

In accordance with the present invention gastroretentive composition is a solid pharmaceutical composition with the effect of slow release, which is stored in the stomach, where the drug has maximum absorption for improved therapeutic effect, acting thus as a system for targeted delivery of drugs.

The composition is useful for both soluble and/or partially soluble or poorly soluble drugs.

Thanks to this specific delivery system drug composition in accordance with the invention is particularly useful for antibacterial compounds belonging to the class of fluoroquinolones, such as cyclopropanation, ofloxacin, pefloxacin, grepafloxacin, enoxacin, amifloxacin, fleroxacin, temafloxacin, lomefloxacin, norfloxacin, sparfloxacin, levofloxacin, Gatifloxacin and moxifloxacin; for amoxicillin and derivatives cephalexin in the form of bases or their salts, as well as for anti-diabetic compounds, such as Metformin hydrochloride, gliclazide; antihypertensive agents, such as diltiazem hydrochloride, metoprolol tartrate or succinate.

The amount of active substance ranges from 10 to 90%, preferably from 20 to 80% and even more preferably from 50 to 75% by weight of the total weight of the composition.

Weak gelling agent is chosen from the group comprising jointly processed microcrystalline cellulose and sodium carboxymethyl cellulose, preferably sold under the trademark AVICELŪ CL611, AVICELŪ RC 581 and AVICELŪ RC 591.

Strong gelling agent is chosen from the group consisting of methylcellulose, hypromellose, hydroxypropylcellulose with the exception nitrosamines hydroxypropylcellulose, hydroxic is cellulose, ethylcellulose, sodium carboxymethyl cellulose, xanthan gum, guar gum, carrageenan, resin carob, sodium alginate, agar-agar, gelatin, modified starches, copolymers carboxyvinyl polymers, a copolymer of acrylates, copolymers of oxyethylene and oxypropylene and mixtures thereof.

The total number of weak and strong gelling funds ranges from 2 to 40%, preferably from 3 to 30% and even more preferably from 5 to 25% by weight of the total weight of the composition.

The ratio of the weak gel-forming means and a strong gel-forming means ranges from 1:1 to 1:10, preferably from 1:2 to 1:8 and more preferably from 1:3 to 1:5.

The ratio of the active substance and the weak and strong gelling funds ranges from 1:99 to 99:1, preferably from 1:1 to 20:1 and even more preferably from 2:1 to 15:1.

Means forming a gas is a compound that forms a gas when it comes into contact with an acidic environment, such as environment of the stomach. The tool forming gas selected from the group consisting of water-soluble carbonates, sulfites and bicarbonates, such as sodium carbonate, sodium bicarbonate, sodium metabisulfite, calcium carbonate and mixtures thereof.

Amount, forming gas, ranges from 5 to 30%, preferably from 10 to 25% and d is more preferably from 12 to 22% by weight of the total weight of the composition.

Means forming a gas, may be present in the composition in accordance with the invention within the granules of the active substance or as excipient composition, or in both.

Thus, in accordance with the first embodiment, at least a part of the forming gas is present within the granules of active substance, i.e. at least a part of the forming gas, granular, together with the active substance and a mixture of weak and strong gel-forming means, optionally with other granulirujushhikh means; the remainder of the funds forming gas, presented in the form of a mixture with eccipienti composition, i.e. degranulation together with the active substance.

In accordance with the second embodiment, the total number of funds, forming gas, is mixed with eccipienti composition, i.e. degranulating together with the active substance and a mixture of weak and strong gel-forming means, optionally with other granulating means.

Gastroretentive composition in accordance with the invention includes an active substance, granulated with a mixture of:

(A) weak gelling means selected from the group including jointly processed microcrystalline cellulose and sodium carboxymethyl cellulose, and

(B) at least one is a high gel-forming means, selected from the group consisting of methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose with the exception nitrosamines hydroxypropylcellulose, hydroxyethyl cellulose, ethyl cellulose, sodium salt of carboxymethyl cellulose, xanthan gum, the guar resin, carrageenan, resin carob, sodium alginate, agar-agar, gelatin, modified starches, copolymers carboxyvinyl polymers, copolymers of acrylates, copolymers of oxyethylene and oxypropylene and mixtures thereof, preferably it is xanthan gum,

(C) optional binders selected from the group consisting of a receiver array with a low viscosity, PVP, copolymer of poly (methacrylic acid (Eudragit E 100) and mixtures thereof,

the composition also includes means forming a gas.

In accordance with a third embodiment of the invention, the active substance may also be granular, at least with one auxiliary agent (D)selected from the group comprising a diluent or an antistatic agent, such as colloidal silicon dioxide or a mixture.

The number of binders (C) ranges from 0 to 10%, preferably from 0.5 to 5% and even more preferably from 1 to 3% by weight of the total weight of the composition.

The granules used in the compositions of the present invention are obtained by wet granulation using alcohol or water-alcohol solution of the specified binders (C). Preferably, the alcohol used for the granulation is ethyl alcohol or isopropyl alcohol.

The composition in accordance with the invention, furthermore, includes excipient selected from the group consisting of diluents, lubricating tools, moisturizing agents, sweeteners, flavorings, colorants, and mixtures thereof.

Commonly used diluent may be lactose, dibasic calcium phosphate, microcrystalline cellulose and mixtures thereof.

As lubrication is generally used stearates, in particular magnesium stearate, glycerinated, colloidal silicon dioxide and a mixture thereof.

Moisturizers can be Polysorbate, laurilsulfate sodium and mixtures thereof.

Preferably the composition in accordance with the invention is a tablet.

Tablets can be coated with a film of suitable polymeric materials that are usually used in this field of technology as the film sheath. Film sheath improves the appearance of the composition, hides unpleasant taste and/or improves the stability of the composition, providing protection from moisture, and does not affect the rate of release of drug from the composition.

The invention also relates to a method of manufacturing a composition in accordance with the invention.

Rela is availa able scientific C with the first embodiment, the method includes the following stages:

(1) the active substance is mixed in dry form with a mixture of (A) weak gel-forming means and (B) a strong gel-forming means, and optionally at least one auxiliary agent (D)selected from the group comprising a diluent or an antistatic agent or a mixture thereof;

(2) optional obtained dry mixture granularit, at least, with one binding agent (S)dissolved in an alcohol solution or mixture of alcohol and water,

(3) means forming a gas are mixed in dry form with the granules obtained in stage (2), optional with eccipienti selected from the group comprising diluents, lubricants, humectants, sweeteners, flavorings, colorants, and mixtures thereof.

(4) the mixture is then pressed into tablets;

(5) optional tablets are covered with a shell.

In accordance with the second embodiment, the method includes the following stages:

(1) the active substance is mixed in dry form with a mixture of (A) weak gel-forming means and (B) a strong gel-forming means, and optionally at least one auxiliary agent (D)selected from the group comprising a diluent or an antistatic agent or a mixture thereof, and at least part of the means forming a gas;

(2) optional is entrusted, the obtained dry mixture granularit, at least, with one binding agent (S)dissolved in an alcohol solution or mixture of alcohol and water,

(3) the remainder of the funds forming the gas, if it exists, is mixed in dry form with the granules obtained in stage (2), optional with eccipienti selected from the group comprising diluents, lubricants, humectants, sweeteners, flavorings, colorants, and mixtures thereof.

(4) the mixture is then pressed into tablets;

(5) optional tablets are covered with a shell.

Hereinafter the invention will be illustrated with examples below.

Information confirming the possibility of carrying out the invention

Example 1

IngredientWeight (mg/tablet)% (wt./wt.)
Metformin hydrochloride510,057,47
Avicel CL 61130,003,45
Xanthan gum145,0016,67
PVP K 3017,001,95
Sodium bicarbonate176,00on 20, 23
Magnesium stearate2,00,23

Metformin hydrochloride (taken for 2% more than the required number), Avicel CL 611, xanthan gum are mixed together in a suitable mixer, such as mixer with large shear force or planetary mixer.

The mixture was granulated with a solution of PVP K 30 in isopropyl alcohol and water. The wet mass was dried in the dryer until then, until he had a moisture content equal to from 3.5 to 5.5%.

The dried mass was calibrated through 20 mesh and mixed in a suitable mixer with sodium bicarbonate and magnesium stearate.

The resulting mixture was pressed into tablets using a rotary tablet press 16 positions (machine type Fette or Suvac) weight tablets 880 mg with the following parameters tabletting:

machine speed: 25 to 27 rpm;

the form of pills - biconvex caletka;

size - length 19 mm, width 9 mm;

strength - from 120 to 160 N.

Tablets were tested for solubility in 0.1 N Hcl using USP apparatus type II at 100 rpm the Results of solubility studies below:

Time in hoursUMMARY percentage release (expressed by weight)
131,10
245,20
465,40
678,00
888,10
1297,70

Example 2

Ciprofloxacin, Avicel CL 611, xanthan gum, colloidal silicon dioxide and sodium bicarbonate are mixed together in a suitable mixer, such as mixer with large shear force or planetary mixer.

The mixture was granulated with a solution of PVP K 30 in isopropyl alcohol. The wet mass was dried in the dryer until then, until he had a moisture content equal to from 1.5 to 3.0%. The dried mass was calibrated through 20 mesh and mixed with magnesium stearate in a suitable mixer. The resulting mixture was pressed into tablets using a rotary tablet press with a weight of tablets 685 mg with the following parameters tabletting:

the form of pills - biconvex caletka;

size - length 16 mm, width 8 mm;

strength of from 100 to 160 N.

Tablets were coated film-forming solution having the following composition (%):

IngredientWeight (mg/tablet)% (wt./wt.)
Ciprofloxacin, base500,0072,99
Avicel CL 61110,001,46
Xanthan gum30,00of 4.38
Colloidal silicon dioxide25,00the 3.65
PVP K 3010,001,46
Sodium bicarbonate85,0012,41
Magnesium stearate25,00the 3.65
The lactose monohydrate19,17
Talc2,87
Titanium dioxide1,43
Polysorbate 800,1
Water76,39

The coating of the tablets was carried out in such a way that it sostav the lo from 1.5 to 2% by weight of the composition in the core tablets.

Tablets were tested for solubility in 0.1 N Hcl using USP apparatus type II at 50 rpm the Results of solubility studies below:

Time in hoursCumulative percentage release (expressed by weight)
137,18
256,09
477,14
692,59
898,26

1. Gastroretentive composition containing the active substance, granulated together with the first gelatinous agent which is a mixture of microcrystalline cellulose with sodium carboxymethyl cellulose, with the second gelatinous agent representing the connection, the viscosity of 1%aqueous solution of which at 25°C. is at least 600 SPS, and gas-forming agent in which the active substance is selected from the antibacterial compounds of the type of fluoroquinolones, such as cyclopropanation, ofloxacin, perfloxacin, grepafloxacin, enoxacin, amifloxacin, fleroxacin, temafloxacin, lomefloxacin, norfloxacin, sparfloxacin, levofloxacin is h, Gatifloxacin, moxifloxacin, amoxicillin and derivatives of cephalexin in the form of its base or salt, and antidiabetic compounds, such as Metformin hydrochloride, gliclazide, and antihypertensive drugs such as diltiazem hydrochloride, tartrate or succinate metoprolol.

2. Gastroretentive composition according to claim 1, in which the second gelatinise agent selected from the group consisting of methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, except hydroxypropylcellulose with a low level of substitution of hydroxyethyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, xanthan gum, guar gum, gum from beans carob, sodium alginate, agar-agar, gelatin, modified starches, copolymers of carboxyquinolone, copolymer of acrylates, copolymers of oxyethylene and oxypropylene and mixtures of the above.

3. Gastroretentive composition according to claim 1 or 2, in which the active ingredient is granulated with (C) a linking agent, and optionally (D) additives selected from the group comprising diluents, antistatic agents or mixtures thereof.

4. Gastroretentive composition according to claim 1 or 2, which also contains excipients selected from the group consisting of diluents, lubricating agents, wetting agents, sweeteners, is somatization, dyes and mixtures of the above.

5. Gastroretentive composition according to claim 1 or 2, in which the gas-generating agent selected from the group consisting of water-soluble carbonates, sulfites and bicarbonates, such as sodium carbonate, sodium bicarbonate, sodium metabisulfite, calcium carbonate and mixtures thereof.

6. Gastroretentive composition according to claim 3, in which the binding agent is selected from the group consisting of a receiver array (hydroxypropylmethylcellulose) with low viscosity, PVP (polyvinylpyridine), copolymer of poly (methacrylic acid (Eudragit E 100) and mixtures thereof.

7. Gastroretentive composition according to claim 1 or 2, in which the amount of the active substance varies from 10 to 90%, preferably from 20 to 80%, more preferably from 50 to 75 wt.% of the total weight of the composition.

8. Gastroretentive composition according to claim 1 or 2, in which the total number of the first and second gelatinous agents ranges from 2 to 40%, preferably from 3 to 30%, more preferably from 5 to 25 wt.% of the total weight of the composition.

9. Gastroretentive composition according to claim 1 or 2, in which the first gelatinous agent to the second gelatinous agent ranges from 1:1 to 1:10, preferably from 1:2 to 1:8, more preferably from 1:3 to 1:5.

10. Gastroretentive composition according to claim 1 or 2, in which the ratio of active substance to the first and second gelatinization ranges from 1:99 to 99:1, preferably from 1:1 to 20:1, more preferably from 2:1 to 15:1.

11. Gastroretentive composition according to claim 1, in which the second gelatinous agent is xanthan gum, and the gas-generating agent sodium bicarbonate.

12. Gastroretentive composition according to claim 1, in which the active ingredient is granulated with PVP.

13. Gastroretentive the composition according to claim 11 or 12, in which the active substance is cyclopropanation or Metformin hydrochloride.

14. Gastroretentive the composition according to claim 11 or 12, in which the amount of active substance ranges from 10 to 90%, preferably from 20 to 80%, more preferably from 50 to 75 wt.% of the total weight of the composition.

15. Gastroretentive the composition according to claim 11 or 12, in which the total number of the first and second gelatinous agents ranges from 2 to 40%, preferably from 3 to 30%, more preferably from 5 to 25 wt.% of the total weight of the composition.

16. Gastroretentive the composition according to claim 11 or 12, in which the first gelatinous agent to the second gelatinous agent ranges from 1:1 to 1:10, preferably from 1:2 to 1:8, more preferably from 1:3 to 1:5.

17. Gastroretentive the composition according to claim 11 or 12, in which the ratio of active substance to the first and second gelatinous agents ranges from 1:99 to 99:1, preferably from 1:1 to 20:1, more prepact the tion from 2:1 to 15:1.

18. Gastroretentive the composition according to 14, in which the active substance is cyclopropanation or Metformin hydrochloride.

19. Gastroretentive the composition according to item 15, in which the active substance is cyclopropanation or Metformin hydrochloride.

20. Gastroretentive the composition according to item 16, in which the active substance is cyclopropanation or Metformin hydrochloride.

21. Gastroretentive the composition according to 17, in which the active substance is cyclopropanation or Metformin hydrochloride.

22. Gastroretentive the composition according to item 13, which also contains excipients selected from the group consisting of diluents, lubricating agents, wetting agents, sweeteners, flavorings, colorants and mixtures thereof.

23. Method of production of the composition according to claim 1 or 2, including:
(1) dry mixing the active substance with a mixture consisting of (A) the first gelatinous agent which is a mixture of microcrystalline cellulose with sodium carboxymethyl cellulose, (B) second gelatinous agent optional at least one additive (D)is selected from the group comprising diluents or antistatics or a mixture thereof, and the gas-generating agent (C) a binding agent;
(2) granulating the obtained dry mixture, at least one binder Agay the volume (S), dissolved in alcohol or in a mixture of alcohol and water;
(3) dry mixing the gas-generating agent with the granules obtained in stage (2), and optionally with excipients selected from the group comprising diluents, lubricating agents, moisturizing agents, sweeteners, flavorings, colorants, and mixtures of the above;
(4) compressing the mixture into tablets;
(5) optional application of a film coating on tablets obtained in stage (4).

24. Method of production of the composition according to claim 1 or 2, including:
(1) dry mixing the active substance with a mixture consisting of (A) the first gelatinous agent which is a mixture of microcrystalline cellulose with sodium carboxymethyl cellulose, (B) second gelatinous agent, optionally at least one additive (D)is selected from the group comprising a diluent or an antistatic agent or a mixture thereof, and at least part of the gas-generating agent;
(2) granulating the obtained dry mixture, at least one binding agent (S)dissolved in alcohol or in a mixture of alcohol and water;
(3) dry mixing the remaining part of the gas-generating agent, if used, with the granules obtained in stage (2), and optionally with excipients selected from the group comprising diluents, lubricating agents, moisturizing agents, podlas Italy, fragrances, dyes, and mixtures of the above;
(4) compressing the mixture into tablets;
(5) optional application of a film coating on tablets.



 

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Solid preparation // 2359661

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns pharmaceutics and medicine and concerns a solid medical product for treatment of diabetes containing a layer, including Pioglitazone, and the layer including Glimepiridum and Polysorbate 80. The agent possesses good indicators of solubility.

EFFECT: development of a preparation with good indicators of solubility.

2 cl, 2 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to pharmaceutical composition of antibiotic, which contains microgranules covered with capsule, and method of their preparation. Said microgranules contain core, which contains clarithromycin, internal layer of capsule, containing at least one cellulose polymer, which is not a polymer of intestine-soluble capsule, in which average size of particles of said covered with capsule microgranules constitutes from approximately 100 to approximately 650 mcm.

EFFECT: antibiotic compositions are described.

16 cl, 9 ex

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