PH-controlled pulsatile delivery system, methods for preparation and use thereof

Abstract

The invention relates to delivery systems that allow for the pulsatile release of a substance, such as a drug, in response to a change in pH. More specifically, it relates to drug administration to the GI tract, in particular to site-specific intestinal drug delivery via the oral route. Provided is a pH-controlled pulsatile release system (PPRS) comprising a core surrounded by a coating layer, wherein said core comprises an active substance and wherein said coating layer comprises a pH-sensitive coating material wherein a swellable agent is embedded. Said swellable agent is capable of taking up at least 1.1 times, preferably at least 5 times, more preferably at least 10 times its weight in water. Also provided is a pharmaceutical composition comprising a PPRS, in particular a colon-specific PPRS.

Claims

1. A release system comprising: a core comprising an active substance, and, surrounding the core, a coating layer comprising a swellable agent embedded in pH-sensitive coating material, wherein the swellable agent is embedded in a continuous matrix of the pH-sensitive coating material at a concentration below the percolation threshold of the swellable agent in the continuous matrix of the pH-sensitive coating material, wherein the swellable agent, in its dry form, is able to take up at least five times its weight in water; and wherein the embedded swellable agent is dispersed within the pH-sensitive coating material in the coating layer and is shielded from fluids by the pH-sensitive coating material.

2. The release system according to claim 1, wherein said swellable agent is selected from the group consisting of sodium starch glycolate and cross-linked carboxymethylcellulose sodium.

3. The release system of claim 1, wherein said pH-sensitive coating material is selected from the group consisting of cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, and co-polymerized methacrylic acid/methacrylic acid methyl esters.

4. The release system of claim 1, wherein said coating layer further comprises an additive.

5. The release system according to claim 1, wherein said active substance is selected from the group consisting of neurotransmitters, L-DOPA, hormone agonists, hormone antagonists, cetrorelix, steroidal or non-steroidal anti-inflammatory drugs, stable isotopes, an immunogenic substance, a vaccine and a combination of any thereof.

6. A method for preparing the release system of claim 1, comprising the steps of: providing a coating solution comprising a mixture of a pH-sensitive coating material and a swellable agent in a solvent or solvent mixture, wherein said coating material is soluble in said solvent and wherein said swellable agent is insoluble and non-swollen in said solvent, applying said coating solution to a solid substrate, and evaporating the solvent of the coating solution resulting in a coating layer where the swellable agent is embedded in a matrix of pH-sensitive coating material.

7. A pharmaceutical composition comprising: the release system of claim 1, and a pharmaceutically acceptable carrier.

8. A method for site specific delivery of a drug, the method comprising: administering to a subject in need thereof a suitable amount of the pharmaceutical composition according to claim 7.

9. The release system of claim 1 wherein the core comprises a pharmaceutically active substance.

10. The release system of claim 1, wherein the swellable agent is able to take up at least 10 times its weight in water.

11. The release system of claim 4, wherein the additive is a plasticizer selected from the group consisting of polyethylene glycol (PEG), triethyl citrate (TEC), and tributyl sebacate (TBS).

12. The method according to claim 6, wherein the solvent or solvent mixture comprises organic solvent, acetone, or isopropyl alcohol.

13. The method according to claim 6, wherein applying the coating suspension to a solid substrate comprises spray coating.

14. The release system of claim 1, wherein the release system is a system selected from the group consisting of a drug delivery system, a colon specific drug delivery system, and a duodenal specific drug delivery system.

15. The method according to claim 8, wherein the site specific drug delivery comprises colon specific and/or duodenal specific drug delivery.

16. A release system, wherein the release system is selected from the group consisting of a drug delivery system, a colon specific active substance delivery system, and a duodenal specific active substance delivery system, said release system comprising: a core comprising a pharmaceutically active substance, and a coating layer surrounding said core, said coating layer comprising: a pH-sensitive coating material selected from the group consisting of cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, and co-polymerized methacrylic acid/methacrylic acid methyl esters, and a swellable agent selected from the group consisting of sodium starch glycolate and cross-linked carboxymethylcellulose sodium, wherein particles of the swellable agent are embedded in a non-percolating way in a continuous matrix of the pH-sensitive coating material at a concentration below the percolation threshold of the swellable agent in the continuous matrix of the pH-sensitive coating material, wherein the swellable agent, in its dry form, is able to take up at least 5 times its weight in water, and wherein the particles of swellable agent are dispersed within the pH-sensitive coating material in the coating layer and are shielded from fluids by pH-sensitive coating material.

17. The method according to claim 6, wherein the coating solution comprises 4% of the swellable agent.

18. The method according to claim 6, wherein the coating solution comprises 5% of the swellable agent.

19. The method according to claim 6, wherein the coating solution comprises 6% of the swellable agent.

20. The method according to claim 6, wherein the coating solution comprises 7% of the swellable agent.

Description

LEGENDS TO THE FIGURES

(1) FIG. 1: Schematic drawing of the proposed mode of action of the swellable agent incorporated in a coating layer. In stage 1, the drug delivery system is exposed to intestinal fluid with a pH>7. The pH-sensitive polymer material in the coating layer starts to dissolve/erode. In stage 2, micro cracks or leakages are formed in the coating layer such that the particles of swellable agent that are present just beneath the surface become wetted. The fluid uptake by the swellable agent results in a dramatic increase of its volume (stage 3), accompanied by a further erosion of the coating layer, enhanced fluid penetration into the coating layer and swelling of the swellable agent. This cascade of events is responsible for a rapid and complete degradation of the coating layer such that the core surface, e.g. a drug capsule, becomes exposed to the environment (stage 4). There is a gradual transition of the initial pH-induced erosion to erosion that relies on exposure of swellable agent to aqueous fluid.

(2) FIG. 2: Release profiles of various registered dosage forms of 5-ASA using the Gastro Intestinal Simulation System (GISS) described in Example 1. Phase I simulates the stomach, phase II the jejunum, phase III the distal ileum and phase IV the colon.

(3) FIG. 3: Average release profile of 6 capsules containing 5-ASA provided with a coating of pH-sensitive polymer (Eudragit S100). Release of 5-ASA was determined over time using the GISS model described in Example 1. For further details see Example 2.

(4) FIG. 4: Average release profile of 6 capsules containing 5-ASA provided with a coating of pH-sensitive polymer (Eudragit S100) and 5% swellable agent (Primojel®). Release of 5-ASA was determined over time using the GISS model described in Example 1. For further details see Example 2.

(5) FIG. 5: Colon-selectivity of a Pulsatile pH-dependent Release System (PPRS) comprising a gelatine capsule with 50 mg of the drug 5-ASA, which capsule was provided with a coating layer (20 mg/capsule) of 7% Eudragit S100/1% PEG6000 and the indicated percentage of swellable agent (Primojel®). CRP-TQR refers to the Total Quantity Released, which is the percentage of 5-ASA released in phase IV, representing the colon, of the total actual release of 5-ASA in phases I through IV. The Colon Released Percentage of the Total Dose (CRP-TD) is the percentage of the total dose released in phase IV. For further details see Example 2.

(6) FIG. 6: Effect of the percentage of swellable agent in the coating suspension on the rate of pulsatile release of the drug. The rate is determined by measuring the time period required to release an average of 50% (T.sub.50) or 70% (T.sub.70) of the total drug dose relative to time zero (T.sub.0) at which <5% drug release was detected.

EXAMPLES

(7) The present invention will be further illustrated by way of the following Examples. These Examples are non-limiting and do not restrict the scope of the invention. A skilled person will understand that many different combinations of pH-sensitive coating materials and swellable agents are suitably used in a pH-controlled pulsatile release system of the invention, of which the specific formulations can be determined empirically.

Example 1

Gastro-Intestinal Simulation System (GISS)

(8) This example describes the gastro-intestinal simulation system which was used by the present inventors to investigate the profiles of drug release of pH-controlled pulsatile drug delivery systems of the invention.

(9) The drug mesalazine (5-ASA) was used as a test drug to evaluate and validate the GISS. 5-ASA is used in the therapy of ulcerative colitis and is readily absorbed in the proximal parts of the intestine. We tested the following commercially available oral dosage forms of 5-ASA: Salofalk® tablets, Salofalk® granules, Asacol® tablets, Pentasa® tablets and granules.

(10) The GISS is a dissolution test which is based on the pharmacopoeial paddle method (apparatus II, Prolabo, Rhône-Poulenc, Paris, France) as described in the USP 26 and Ph. Eur. IV. During the test, a drug formulation is exposed to four phases simulating in subsequent order the stomach, the jejunum, distal ileum, and the proximal colon. Table 1 gives the specifications of these phases as well as the biorelevant media which were applied. The paddle was operated at 50 RPM and the system was kept at a temperature between 37±° C.

(11) TABLE-US-00001 TABLE 1 Specifications of the four phases of the GISS Volume Residence Osmolality Phase GI-Segment (mL) time (hour) pH (mosmol/kg) I Stomach Simulated Gastric Fluid sine 500 2.0 1.2 ± 0.10 150 ± 25 pepsin (USP 26) II Jejunum Simulated Intestinal Fluid sine 629 2.0 6.8 ± 0.10 250 ± 50 pepsin (USP 24) + sodium chloride III Ileum (distal) Simulated Intestinal Fluid sine 940 0.5 7.5 ± 0.10 250 ± 50 pepsin (USP 23) + sodium chloride IV Colon Simulated Colonic Fluid 1000 1.5 6.0 ± 0.10 250 ± 60 (proximal)

(12) The buffering capacity was tested by measuring the pH in a GISS with and without 5-ASA. It was also tested whether the osmolality remains within specification during dissolution tests.

(13) Release Measurements

(14) The release profile of the modified oral dosage forms was determined by measuring the concentration of 5-ASA spectrophotometrically using an Ultraspec 4052 TDS apparatus (LKB, Zoetermeer, The Netherlands). The specific extinction of 5-ASA in each phase was determined (n=5) at λ=331 nm (Table 2.). If the concentration measured were out of the linear detection range, absorbance was measured off line after dilution of the sample with 3 N hydrochloric acid and subsequent measurement at λ=303 nm. The specific extinction of 5-ASA is then 236.0.

(15) TABLE-US-00002 TABLE 2 Specific extinction of 5-ASA per phase Phase Specific extinction at λ = 331 nm I 17.3 II 209.5 III 218.2 IV 161.4
Calculations

(16) Release rates were calculated by dividing the amount released per phase by the residence time. Colon selectivity can be expressed by 3 different parameters. The Colon Released Percentage of the Total Quantity Released (CRP-TQR), which is the percentage released in phase IV of the total release in phase I until IV. Secondly, the Colon Released Percentage of the Total Dose (CRP-TD) is the percentage of the dose released in phase IV. Thirdly, the Colonic Selectivity Ration (CSR) is a dose-independent parameter indicative of the colon selective release of the dosage form relative to the other three release phases of the GISS. It is calculated by dividing the fraction released in phase IV by the cumulative fraction in the earlier three phases.

(17) Results

(18) Gastro-Intestinal Simulation System

(19) An important aspect of in vitro dissolution testing of pH-controlled dosage forms is that there may only be a limited influence of the compound being released on the pH itself. In table 3 it is shown that the GISS has enough buffering capacity to keep the pH within the specified range (see Table 1) during the release of 5-ASA in the four phases. Furthermore, the osmolality remained within specification (Table 1), irrespective of the presence of 50 mg of 5-ASA.

(20) TABLE-US-00003 TABLE 3 Average pH ± standard deviation measured in GISS n I II III IV Blank 2 1.21 ± 0.01 6.85 ± 0.03 7.54 ± 0.01 6.29 ± 0.00 500 mg 5-ASA 2 1.22 ± 0.00 6.67 ± 0.03 7.31 ± 0.05 6.10 ± 0.05 Salofalk.sup.(r) Tablet MSR 500 MG 6 1.16 ± 0.01 6.85 ± 0.02 7.52 ± 0.05 n.m..sup.1 Salofalk.sup.(r) Granustix in Sachet 6 1.18 ± 0.01 6.86 ± 0.01 7.67 ± 0.01 5.89 ± 0.01 1000 MG Asacol.sup.(r) Tablet MSR 400 MG 5 1.12 ± 0.00 6.63 ± 0.06 7.25 ± 0.05 6.12 ± 0.06 Pentasa.sup.(r) Tablet Retard 500 MG 6 1.14 ± 0.02 6.65 ± 0.02 7.34 ± 0.03 5.97 ± 0.04 Pentasa.sup.(r) Granules in Sachet 1 G 6 1.23 ± N.A. 6.79 ± N.A. 7.54 ± N.A. 5.77 ± N.A. .sup.1Not measured
3.2 Release Profiles

(21) In FIG. 2, the release profiles of the tested products are shown. As would be expected, the products with a pH-sensitive coating (Salofalk® tablets, Salofalk® granules and Asacol® tablets) do not release any 5-ASA in the simulated stomach under fasted conditions (phase I). Furthermore, it is shown that Salofalk® tablets release 5-ASA more proximal than Asacol® tablets. Both do not release much 5-ASA in the simulated proximal colon. Pentasa® tablets as well as Pentasa® granules release a substantial amount (50-70%) of 5-ASA during a 2 hour stay in SGFsp (USP 26). Moreover, both Pentasa® tablets and Pentasa® granules release 5-ASA in the simulated stomach 3 to 5 times faster than in the simulated small and large intestine (Table 4.). Salofalk® granules show a lag time after which the release starts with zero-order kinetics. All products perform according to their pharmaceutical technological concepts.

(22) TABLE-US-00004 TABLE 4 Release rates during the different phases for the tested products (standardised to a dose of 500 mg) Release rate (mg/min per phase) I II III IV Salofalk.sup.(r) Tablet MSR 500 MG 0.0 4.3 0.8 0.0 Salofalk.sup.(r) Granustix in Sachet 1000 0.1 1.2 2.5 0.4 MG Asacol.sup.(r) Tablet MSR 400 MG 0.0 3.3 2.2 0.2 Pentasa.sup.(r) Tablet Retard 500 MG 2.1 0.5 0.6 0.1 Pentasa.sup.(r) Granules in Sachet 1 G 2.8 0.6 0.6 0.2

(23) In Table 5 the colon selectivity is given for each product. The data show that the actual colonic selectivity of the products is rather poor. Only the pellet products show a certain degree of colonic selectivity.

(24) TABLE-US-00005 TABLE 5 CRP-TQR and CRP-TD for the tested products Product CRP-TQR CRP-TD Salofalk Tablet MSR 500 MG 0.0% 0.0% Pentasa Tablet Retard 500 MG 3.3% 2.2% Asacol Tablet MSR 400 MG 3.8% 3.7% Pentasa Granules in Sachet 1 G 4.7% 4.1% Salofalk Granustix in Sachet 1000 MG 14.8% 6.8%
Conclusions

(25) The release profiles of all products are in agreement with their technological concepts and with available in vivo data. The percentage of the dose released in the simulated colon is small in all products. The GISS is a robust system able to discriminate between different types of modified-release oral dosage forms. It reveals release profiles with in vivo relevance and is thus suitably used for the evaluation of site-specific delivery systems of different substances.

Example 2

Development of a Pulsatile pH-Controlled Release System (PPRS)

(26) This example demonstrates the beneficial effects of embedding a swellable agent (in this case sodium starch glycolate sold under the trade name Primojel) in a coating layer of pH-sensitive enteric coating material.

(27) Materials and Methods

(28) A standard coating solution was prepared comprising 7% poly-acrylate resin (Eudragit S100) and 1% PEG6000 in a solvent mixture of acetone/water [97:3; by volume]. The standard coating solution was supplemented with various amounts (1, 2, 3, 4, 5, or 10% (w/v) of Primojel to produce different coating suspensions. In a second experiment, capsules were coated with an improved coating procedure. The standard coating solution was supplemented with various amounts (4, 5, 6, 7% w/v) of Primojel.

(29) The coating suspensions were applied by spray coating (Capsule Coater, Labo Tech) onto hard gelatine capsules in an amount of 20 grams coating suspension per 20 capsules. The capsules comprised 50 mg 5-ASA and Avicel™. The charge size was 20 capsules. Following the coating step, the capsules underwent a heat treatment of 1 hour at 50° C. to allow evaporation of the solvent mixture and curring of the polymeric film such that a composite coating layer was formed around the capsules.

(30) Tests Performed

(31) The GISS described in Example 1 was used to investigate the release profiles of 5-ASA from each batch of coated capsules. The average release profiles were determined on line by determining every 3 minutes the concentration of 5-ASA using spectrophotometry at 331 nm (n=6).

(32) Calculations

(33) The release rate is being expressed as the time needed tot release 50% (t.sub.50) respectively 70% (t.sub.70) of the content, calculated form the last measurement below 5%. The colon selectivity is being expressed by three parameters:

(34) 1. the colon released percentage of the total quantity released (CRP-TQR)

(35) 2. the colon released percentage of the total dose (CRP-TD)

(36) Results

(37) FIG. 3 shows the average geometric mean of the release profiles of five individual capsules that were coated the standard coating solution, i.e. without swellable agent. FIG. 4 shows the average release profiles of six individual capsules provided with 20 g of a coating layer comprising 5% swellable agent. Capsules coated without swellable agent exhibit insufficient release of 5-ASA (50.4%) after 360 min in the GISS. In addition, a large variation in the released dose is observed (5 to 98%). The addition of swellable agent to the coating suspension results in a pulsatile release profile, after a lag phase of around 240 minutes. Clearly, the presence of the swellable agent in the coating layer enhances the rate of drug release from the capsule, reduces the inter-capsule variation, enhances the CRP-TD. In Table 6 all data are shown.

(38) TABLE-US-00006 TABLE 6 Characterization of capsules provided with a coating comprising varying concentrations of the swellable agent Primojel. % Release Release CRP- Primojel t50 t70 (t = 270) (t = 360) CRP-TD TQR 0%  78 min 135 min 7.8% 58.2% 50.4% 94% 1% 106 min 151 min 1.5% 31.4% 29.9% 96% 2% 397 min 556 min 1.7% 14.1% 12.4% 88% 3% 167 min 242 min 3.6% 29.0% 25.4% 90% 4% 108 min 501 min 9.2% 48.8% 39.6% 80% 5%  38 min  45 min 16.2% 98.2% 82.0% 81% 10%   36 min  74 min 28.8% 77.6% 48.8% 56%

(39) The influence of the amount of swellable agent in the coating layer on the colon-selective drug release is graphically shown in FIG. 5. Colon selectivity is expressed in CRP-TQR and CRP-TD (see for abbreviations Example 1). Capsules coated with standard coating solution comprising 0-5% Primojel display a CRP-TQR of more than 80%. The CRP-TQR is lower in capsules coated with 10% Primojel in the coating suspension. Only at a concentration of 5% Primojel, a large fraction of the total drug dose is released in the simulated proximal part of the colon, as reflected by a high CRP-TD. An average of 82% of the total dose of 5-ASA is released in phase IV of the GISS, while the other capsules tested only released up to 50% in phase IV.

(40) FIG. 6 demonstrates the effect of the percentage of Primojel in the coating suspension on the rate of pulsatile release of the drug. This rate is determined by measuring the time period required to release an average of 50% (T.sub.50) or 70% (T.sub.70) of the total drug dose relative to time zero (T.sub.0) at which <5% drug release was detected.

Example 3

Optimalisation of the PPRS

(41) This Example describes an optimalisation of the procedure described in Example 2 for the manufacture of a pulsatile pH-controlled release system. The optimalisation involved primarily mechanical aspects of the coating process, such as shortening of the inlet and outlet tubing, prerunning of the pump and the use of standardised glasswork and stirring bar for the supply of coating suspension. Furthermore, a swellable agent was included not only in the coating layer but also in the core.

(42) Materials and Methods

(43) Gelatine capsules filled with avicel, 50 mg 5-ASA and 5% Primojel were coated with a coating suspension comprising 7% Eudragit S100 and 1% PEG 6000 in a mixture of acetone/water [97:3]. The coating suspension furthermore contained 4, 5, 6 or 7% [m/v] Primojel. The capsules were coated with 20 grams of coating suspension as described in Example 2. Each batch comprising 20 capsules was tested in the GISS described in Example 1 to determine the release profile of 5-ASA.

(44) Results

(45) Colon-selective release was expressed as CRP-TQR and CRP-TD (see Example 1 for explanations of these abbreviations). As indicated in Table 7, drug release from capsules coated with 4 or 5% Primojel occurred for nearly 90% in phase IV of the GISS (CRP-TQR). The remainder was released in phase 3. Drug release in the simulated proximal part of the colon of the capsules coated with 4 or 5% Primojel was found to be 67% and 59% of the total dose, respectively (CRP-TD). Both parameters decreased with an increase of the percentage Primojel in the coating due to a shortened opening time of the coating. For capsules with 6 or 7% Primojel the onset of release occurred in the second phase of the GISS (T.sub.0 was 155 and 149 minutes, respectively). The early erosion resulted in an early disruption of the coating during phase III. In contrast, the T.sub.0 of the 4 and 5% capsules was 186 and 183 minutes, respectively.

(46) TABLE-US-00007 TABLE 7 data of measurements of capsules coated according to the improved coating procedure as described in Example 3. % Release Release CRP- Primojel T.sub.50 T.sub.70 (t = 270) (t = 360) CRP-TD TQR 4% 40 min 63 min  6.4% 87.4% 81.0% 89% 5% 54 min 87 min  8.3% 78.3% 70.0% 89% 6% 30 min 38 min 31.0% 87.6% 56.6% 58% 7% 28 min 43 min 30.6% 87.8% 57.2% 50%

(47) All capsules tested displayed a pulsatile drug release profile, as is illustrated by the T.sub.50 and T.sub.70 values represented in Table 7. Capsules coated with 4% Primojel coating suspension released 70% of the drug within 67 minutes from the onset of drug release. An increase of the percentage of Primojel was accompanied by a decrease in the rate of drug release; the inclusion of 7% Primojel in the coating suspension yielded a T.sub.70 of 99 minutes. In conclusion, although all percentages tested displayed a good pulsatile release profile, the concentration of 4 or 5% Primojel works best with regards to (simulated) colon-specific release.

Example 4

(48) This Example describes the use of a second type of swellable agent. A standard coating solution was prepared comprising 7% poly-acrylate resin (Eudragit S100) and 1% PEG6000 in a solvent mixture of acetone/water [97:3; by volume]. The standard coating solution was supplemented with various amounts (0, 3 and 5%) of Ac-Di-Sol™ as swellable agent to produce different coating suspensions. The coating suspensions were applied by spraycoating (Capsule Coater, Labo Tech) onto gelatinised capsules in an amount of 50±5 mg dry coating material per capsule. The capsules comprised 50 mg 5-ASA, avicel and 5% Primojel™. The charge size was 20 capsules. Following the coating, the capsules underwent a heat treatment of 1 hour at 50° C. to allow evaporation of the solvent mixture and curring of the polymeric film such that a composite coating layer was formed around the capsules.

(49) The capsules were tested in the GISS described in Example 1 to investigate the release profiles of 5-ASA from each batch of coated capsules.

(50) Results:

(51) Table 8 shows the results of the release measurements performed on the capsules containing different Ac-Di-Sol amounts. Given in the table are the total amount of drug released during the test (Released), the time at which the drug release started (T.sub.0), the time needed to release 50% of the drug after the release was started (T.sub.50), the time to release 70% of the drug (T.sub.70) and the Colon Released Percentage of the Total Quantity Released (CRP-TQR).

(52) TABLE-US-00008 TABLE 8 Results of the drug release studies with Eudragit S100 coatings containing different amounts of Ac-Di-Sol Released T.sub.0 T.sub.50 T.sub.70 CRP- (%) (min) (min) (min) TQR Ac-Di-Sol 0% 19 255 >105 >105 — Ac-Di-Sol 3% 94 246 18 27 36 Ac-di-Sol 5% 87 243 17 28 26

(53) The results clearly show that inclusion of the Ac-Di-Sol to the coating increases the pulsatile character of the drug release and increases the amount of drug delivered to the colon.

Example 5

(54) In another embodiment an aqueous dispersion of the following composition was made:

(55) TABLE-US-00009 Water 22.71 g  Eudragit S100 8.43 g Ammonia (1 M) 4.29 g Triethyl Citrate 4.22 g Primojel ™ 0.12 g

(56) The dispersion rapidly turned into a highly viscous mass which could not be sprayed onto tablets, capsules or pellets. This indicates that the use of an aqueous solvent is not suitable for the production of the system described in this application.