pH-dependent gradual release pharmaceutical composition

Abstract

The invention concerns a pH-dependent gradual sustained release composition for increasing the pH in the upper part of the small intestines. Particles of the composition are provided with a multilayer polymer coating of specific structure which ensures the gradual release of the active agent in the range of pH 4.5 to 5.5. A process for preparing said composition is also claimed.

Claims

1. A pH dependent gradual release pharmaceutical composition for increasing the actual pH of the duodenum and the upper part of the jejunum by releasing sodium hydrogen carbonate there, which composition comprises a first and a second type of microparticles having multilayer enterosolvent coatings, wherein the first type of microparticles comprises a cationic polymer coating insoluble above pH 5 (coating “a”), a polymer coating soluble at pH≧6 (coating “A”), a pH-independent polymer coating (coating “B”) and an anionic polymer coating soluble at pH≧4.5 (coating “C”), and the second type of microparticles comprises a cationic polymer coating insoluble above pH 5 (coating “a”), a polymer coating soluble at pH≧6 (coating “A”), a pH-independent polymer coating (coating “B”) and an anionic polymer coating soluble at pH≧5.5 (coating “D”) and the cores of microparticles comprising sodium hydrogen carbonate, which first type of microparticles disrupts and releases sodium hydrogen carbonate at a threshold value of pH 4.5, and which second type of microparticles disrupts and releases sodium hydrogen carbonate at a threshold value of pH 5.5.

2. The composition according to claim 1, wherein the ratio of the first and second types of microparticles is 20/80 to 80/20.

3. The composition according to claim 1, which composition is filled in an gastrosolvent capsule.

4. The composition according to claim 1, wherein coating “a” comprises an aminoalkyl methacrylate copolymer, coating “A” comprises a copolymer of methacrylic acid and methacrylate, coating “B” comprises a copolymer of ethyl acrylate and methyl acrylate, coating “C” comprises hydroxypropyl methylcellulose phthalate and coating “D” comprises a copolymer of methacrylic acid and ethyl acrylate, and wherein the ratio of the first and second types of microparticles is 50/50.

5. The composition according to claim 1 for the treatment and prevention of disorders, wherein the actual amount of the bicarbonate available in the lumen of the small intestine is not sufficient for neutralizing the gastric acid or the acidic chymus and wherein the motility of the alimentary tract is disturbed.

6. A process for the preparation of the composition according to claim 1 characterized by preparing the particle cores from sodium hydrogen carbonate and commonly used pharmaceutical additives by alcoholic granulation under anhydrous conditions, then converting them to the first and second types of microparticles by consecutively applying the coating layers of the given type of microparticle, wherein coatings “a” and “A” are applied in the form of alcoholic solutions and coatings “B”, “C” and “D” are applied in the form of aqueous solutions or dispersions, after that the diverse types of microparticles are mixed and optionally filled into gastrosolvent capsules.

7. A method for increasing the pH of the duodenum and the upper part of the jejunum of a patient, said method comprising orally administering the pharmaceutical composition of claim 1 to the patient and thereby releasing sodium hydrogen carbonate in said duodenum and/or said upper part of the jejunum of said patient upon the disrupting of both of said types of microparticles there.

8. The method of claim 7, wherein the actual amount of the bicarbonate available in the lumen of the small intestine of the patient is not sufficient for neutralizing the gastric acid or the acidic chymus and wherein the motility of the alimentary tract is disturbed.

9. The method of claim 7, wherein the pharmaceutical composition is administered in combination with pancreatic digestive enzymes.

10. The composition according to claim 1, wherein, upon disrupting, said first and second types of microparticles release sodium hydrogen carbonate without delay.

11. The composition according to claim 1, wherein the ratio of the first and second types of microparticles is in the range of about 1:1 to about 2:1, which composition releases sodium hydrogen carbonate at pH 4.5 within about 30 min and at pH 5.5 within 15 to 20 min.

12. The method of claim 7, wherein, upon disrupting, said first and second types of microparticles begin releasing sodium hydrogen carbonate without delay.

13. The method of claim 7, wherein the ratio of the first and second types of microparticles is in the range of about 1:1 to about 2:1, and wherein said composition completely releases the sodium hydrogen carbonate at pH 4.5 within about 30 min and at pH 5.5 within 15 to 20 min.

Description

FIGURES

(1) FIG. 1 shows the structure of the multilayer coatings of the microparticles according to the invention;

(2) FIGS. 2a) to 2c) show the pH changes in the function of time on account of the active agent released from the microparticles in three solutions with diverse initial pH values, where the initial pH values were pH 3, pH 4.5 and pH 5.5 in FIGS. 2a), 2b) and 2c), respectively.

(3) The examples below are disclosed solely by way of illustration; the scope of the invention is not limited to the contents of the examples.

EXAMPLES

Example 1

(4) Preparation of a Composition Comprising MP-4.5 and MP-5.5 in Ratio 1:1.

(5) 1.1 Preparing MP Comprising NaHCO.sub.3

(6) In the preparation of 1000 g NaHCO.sub.3 pellet core the following items are measured:

(7) TABLE-US-00001 NaHCO.sub.3 809.0 g Avicel PH 101 124.3 g Kollidon VA 64 66.7 g Ethanol (96%) 336.0 g

(8) The components are homogenized in a high shear mixer at 900 rpm for 5 minutes. After homogenization, granulating material Kollidon VA64 in ethanol is sprayed at 900 rpm, with applying speed of 11.5 g/min, then pelletized at 900 rpm for 15 minutes. The resulted pellets are provided with multilayer coatings of aABC or aABD structure as described below.

(9) 1.2 Applying the Coating Layers

(10) Preparation of coatinging solutions “a” and “A”:

(11) Eudragit powder is dissolved at room temperature by adding small portions to alcohol while stirring continuously. The dissolution period is 30 min. The agitation is carried out using a magnetic bar stirrer.

(12) Coating “a”: Solution of Eudragit E100 in ethanol

(13) Composition of the Coating Solution:

(14) TABLE-US-00002 Eudragit E100 33 g Ethanol 96% ad 264 g

(15) Coating “A”: Solution of Eudragit L100 in ethanol

(16) Composition of the Coating Solution:

(17) TABLE-US-00003 Eudragit L100 33 g Ethanol 96% ad 264 g

(18) Coating parameters (for 150 g):

(19) TABLE-US-00004 Setting temperature: 35° C. Input air temperature: 35° C. ± 3° C. Output air temperature: 29° C. ± 3° C. Spraying air pressure: 0.9 bar Spraying speed: 2.2 g/min Speed of fluid air: 80 m.sup.3/h

(20) Preparing dispersion “B”:

(21) 30% polymer dispersion is mixed with water, then talc is dispersed therein while stirring continuously, after that the mixture is homogenized for 30 minutes.

(22) Coating “B”: Eudragit NE30D

(23) Composition of the Coating Dispersion:

(24) TABLE-US-00005 Eudragit NE30D 28.5 g Talc 4.25 g Demineralized water 28.5 g

(25) Coating parameters (for 150 g):

(26) TABLE-US-00006 Setting temperature: 10° C. Input air temperature: 25° C. ± 2° C. Output air temperature: 20° C. ± 2° C. Spraying air pressure: 0.8 bar Spraying speed: 2.7 g/min Speed of fluid air: 50 m.sup.3/h

(27) Preparing dispersion “C”:

(28) HPMCP-50 powder is dissolved in the mixture of alcohol and water while stirring continuously.

(29) Coating “C”: HPMCP-50

(30) Composition of the Coating Solution:

(31) TABLE-US-00007 HPMCP-50 20 g Demineralized water 36 g Ethanol 96% ad 200 g

(32) Coating parameters (for 150 g):

(33) TABLE-US-00008 Setting temperature: 32° C. Input air temperature: 32° C. ± 2° C. Output air temperature: 28° C. ± 2° C. Spraying air pressure: 0.8 bar Spraying speed: 1.8 g/min Speed of fluid air: 100 m.sup.3/h

(34) Preparing dispersion “D”:

(35) Triethyl citrate is dispersed in water, then talc is dispersed in it while stirring continuously, after that they are mixed with 30% polymer dispersion, and the mixture is homogenized for 30 minutes.

(36) Coating “D”: Eudragit L30-D55

(37) Composition of the Coating Dispersion:

(38) TABLE-US-00009 Eudragit L30-D55 159.0 g Talc 24.0 g Triethyl citrate 4.8 g Demineralized water ad 300.0 g Weight of the pellet: 114 g

(39) Coating parameters:

(40) TABLE-US-00010 Setting temperature: 25° C. Input air temperature: 30° C. ± 2° C. Output air temperature: 23° C. ± 2° C. Spraying air pressure: 1 bar Spraying speed: 2.8 g/min Speed of fluid air: 50 m.sup.3/h

(41) The microparticles prepared according to the foregoing are mixed in ratio 1:1 and filled in gastrosolvent capsules, in portions of 1 g/capsule.

Example 2

(42) Preparation of a Composition Comprising MP-4.5 and MP-5.5 in 2:1 Ratio.

(43) MP-4.5 and MP-5.5 were prepared just as described in Example 1, and the two types of coated final micropellets are mixed in 2:1 ratio and filled in capsules.

Example 3

(44) Dissolution Experiments

(45) Dissolution experiments were carried out using standard rotating vane method according to the European Pharmacopoeia in 900 ml hydrochloride solution, pH 3, and phosphate blunting solutions, pH 4.5 and pH 5.5, respectively, on 37±0.5° C., at a mixing speed of 50 rpm.

(46) In the experiment 2.0 g sample was measured (sodium bicarbonate content ˜1.0 g) and the pH change was registered continuously using Microprocessor pH Meter pH 210 (Hanna Instruments, Woonsocket, US), measuring precision: ±0.01 pH value.

(47) FIGS. 2a) to 2c) show the pH modifying effects of the samples in three solutions with diverse initial pH values, in the function of time, where the results of the experiments started at initial pH values of pH 3, pH 4.5 and pH 5.5 can be seen on FIGS. 2a), 2b) and 2c), respectively.

(48) As it is shown on FIG. 2a), in the medium having initial pH 3 the acidic initial pH value remained essentially unchanged in the presence of MP-4.5, i.e. the sample coated with aABC, and in the presence of 1:1 mixture of MP-4.5/MP-5.5, i.e. the sample including coatings in ratio of aABC/aABD in 1/1 ratio, and the pH increased significantly only after 90 minutes, while in the presence of the sample coated with aABD, the pH value of the medium increased only slightly even after this period.

(49) As it is shown on FIG. 2b), in the medium having initial pH 4.5 the mixture of particles with two types of coatings released bicarbonate most quickly (˜30 min), it was followed by MP-4.5, and sodium bicarbonate was released from MP-5.5 lastly (90 min).

(50) On FIG. 2c) the results obtained in the solution having initial pH 5.5 can be seen, where both the MP-4.5 and the mixed sample released sodium bicarbonate within 15 to 20 minutes, while MP-5.5 released sodium bicarbonate more slowly.

(51) In the dissolution experiments of the 2:1 mixture of MP-4.5/MP-5.5 carried out under similar conditions we have got the following results (not shown in the figures).

(52) In the medium having initial pH 4.5, the 2:1 mixture of particles with two types of coatings released bicarbonate within about 30 to 40 minutes, similarly to the 1:1 mixture.

(53) In the medium of pH 5.5, the sample of 2:1 mixture released sodium bicarbonate within 15 minutes, which was a little faster than in the case of the sample of 1:1 mixture.

(54) Firstly, the above results clearly show that both types of coatings fully hinder the release of sodium bicarbonate in the acidic environment of the stomach. This result is attained by the use of cationic protecting layer “a”. Secondly, both MP-4.5 and the mixtures of MP-4.5/MP-5.5, that is, 1:1 and 2:1 mixtures provide adequate protection in the acidic environment of the stomach, but are able to decrease the hydrogen ion concentration at a higher pH value, which is of great importance in view of the long residence time in the duodenum.