Solid dosage forms comprising an enteric coating with accelerated drug release

Abstract

The present invention provides a solid dosage form including an inner coating located between a core containing a pharmaceutically active ingredient and an outer enteric coating; wherein the inner coating includes a partially neutralized anionic polymeric material, and at least a carboxylic acid having 2 to 16 carbon atoms the salts thereof or mixtures of the acid and its salt; wherein the outer coating includes an anionic polymeric material which is less or not at all neutralized than the material of the inner coating.

Claims

1. A solid dosage form comprising an inner coating located between a core containing a pharmaceutically active ingredient and an outer enteric coating; wherein said inner coating comprises a partially neutralized anionic polymeric material, and at least a carboxylic acid having 2 to 16 carbon atoms, the salts thereof or mixtures of said acid and its salt; wherein said outer coating comprises an anionic polymeric material which is less neutralized than the material of the inner coating or not at all neutralized.

2. The solid dosage form according to claim 1, wherein the difference in the neutralization between the inner coating and the outer coating is at least 5 percentage points.

3. The solid dosage form according to claim 1, wherein the degree of neutralization of anionic groups of the outer coating is at most 10 percent.

4. The solid dosage form according to claim 1, wherein the anionic polymeric material of the inner coating and the outer coating, respectively, is independently selected from the group consisting of polymethacrylates, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate (HPMC-AS), cellulose acetate trimellitate, and shellac.

5. The solid dosage form according to claim 1, wherein the inner coating is made of a partially neutralized anionic (meth)acrylate copolymer consisting of free-radical polymerized units of 25 to 95% by weight C.sub.1- to C.sub.4-alkyl esters of acrylic or methacrylic acid and 5 to 75% by weight (meth)acrylate monomers having an anionic group, wherein 1 to 80% of the contained anionic groups are neutralized by an alkaline agent; and wherein the outer coating is made of an anionic (meth)acrylate copolymer consisting of free-radical polymerized units of 25 to 95% by weight C.sub.1- to C.sub.4-alkyl esters of acrylic or methacrylic acid and 5 to 75% by weight (meth)acrylate monomers having an anionic group.

6. The solid dosage form according to claim 1, wherein the salt is an alkali metal salt, an alkaline earth metal salt, an ammonium salt or a soluble metal salt.

7. The solid dosage form according to claim 1, wherein the carboxylic acid having 2 to 16 carbon atoms comprises 1, 2 or 3 carboxyl groups.

8. The solid dosage form according to claim 1, wherein the carboxylic acid is selected from the group consisting of sorbic acid, benzoic acid, fumaric acid, adipic acid, citric acid, succinic acid, glutaric acid, malic acid, tartaric acid, acetic acid, glycolic acid, malonic acid, propanoic acid, glyceric acid, trans-crotonic acid, itaconic acid, mesaconic acid, trimethylacetic acid, isocitric acid, hexanoic acid, 4-methylpentanoic acid, gallic acid, terephthalic acid, phenylacetic acid, mandelic acid, alpha-phenylpropanoic acid, beta-phenylpropanoic acid, lauric acid, caprylic acid, caprinic acid, myristic acid and mixtures thereof, the salts thereof and mixtures of said acid and its salt.

9. The solid dosage form according to claim 1, wherein the carboxylic acid is adipic acid or citric acid.

10. The solid dosage form according to claim 1. wherein each of the inner and the outer coatings contain 2 to 10 mg/cm.sup.2 polymer weight gain.

11. The solid dosage form according to claim 1, wherein the relation between the inner and the outer coating is 10:90 to 90:10 by weight of dry polymer.

Description

EXAMPLES

(1) 1. General Findings

(2) In order to find a solution to the object of the present invention the inventors found that for example a dispersion of Eudragit L 30D-55 containing 10 percent by weight adipic acid, which was neutralized to pH 5.6 could change to a clear solution and the so cast film dissolved very fast in pH 5.8 phosphate buffer. The respective film swelled and turned to clear within 5 min. However, neutralized adipic acid could leach out from the film in 0.1M HCl, which makes the film performance in subsequent phosphate buffer no difference as control film.

(3) Further exploration resulted in the present invention. According to the present invention the application of a normal Eudragit L 30D-55 coat on top of the neutralized adipic acid-containing coat of solid dosage forms, the outer

(4) Eudragit coat protects the inner coat containing adipic acid in 0.1M HCl. During the subsequent treatment of the respective pellets or tablets in phosphate buffer having for example a pH of 5.6, the buffer solution will diffuse through the outer coat and contact the inner coat. As result the adipic acid-containing inner coat could dissolve very fast and assumingly could diffuse into the outer coat, therefore helping to break down the outer coat as well and to release the drug.

(5) 2. Materials

(6) Prednisolone was purchased from Aventis Pharma., Antony, France. Theophylline pellets (1.00-1.25 mm) were purchased from Klinge Pharm. Lactose (Pharmatose, 110 m) was purchased from Ellis & Everard, Essex, UK. Sodium carboxymethylcellulose (Ac-di-sol) was donated by FMC International, Cork, Eire. Polyvinylpyrrolidone (PVP) was purchased from VWR International Ltd, Poole, UK. Eudragit L 30D-55 (Rhm GmbH & Co. KG, Darmstadt, Germany). HPMC E5 (hydroxylpropyl methylcellulose) was donated by Colorcon Inc., Dartford, UK. HP-55 (hydroxypropyl methylcellulose phthalate) was purchased from Shin-Etsu Chemical Co., Ltd, Tokyo, Japan. Triethyl citrate (TEC) was purchased from Lancaster Synthesis, Lancashire, UK. All other reagents were purchased from Sigma, St. Louis, Mo., USA.

(7) 3. Preparation of Prednisolone Tablets and Pellets

(8) As solid dosage form tablets containing the active substance Prednisolone were used in the tests. The round tablets (representing the core of the solid dosage form) with a diameter of 8 mm were prepared by wet granulation. Each tablet contains 5% by weight prednisolone (10 mg), 88.5% by weight lactose, 5 by weight PVP, 0.5 percent Ac-di-sol and 1% by weight magnesium stearate. The obtained tablets are further coated by the respective layers.

(9) Prednisolone pellets (0.71-1.0 mm) were prepared by extrusion and spheronisation. Each pellet contains 35% by weight prednisolone, 40% by weight lactose and 25% by weight Avicel PH101.

(10) 4. Coating for Prednisolone Tablets and Pellets

(11) Prednisolone tablets and pellets were coated in fluid bed (Strea-1, Aeromatic).

(12) 4.1 Coating Formulations

(13) Eudragit L 30D-55 with Organic Acid Inner Coating:

(14) Adipic and citric acid, respectively, (5 to 30%, based on polymer weight), 5% triethylcitrate (TEC) based on polymer weight were dissolved in water, and added into Eudragit L30D-55 dispersions. The above dispersions were then neutralised to pH 5.6, 5.8 or 6.0 using 1 M NaOH and the dispersions turned to clear solutions. 50% talc based on the polymer weight was homogenised in water and added to above solution. The total solid content of the coating dispersion was 10%. 5 mg/cm.sup.2 of polymer was applied.

(15) Eudragit L100 with Organic Acid Inner Coating

(16) 10% citric acid and 50% TEC (both based on polymer weight) were dissolved in water. Eudragit L100 was dispersed in above solution, and neutralized to clear solution with pH 6.2 or 6.8.50% Talc based on polymer weight was homogenized in water and added to above solution. The total solid content of the coating dispersion was 10%. 5 mg/cm.sup.2 of polymer was applied.

(17) HPMC as Coating:

(18) 10% by weight HPMC E5 solutions with or without 10% by weight Na citrate, 10% citric acid, 10% NaCl were used. 1, 3, 5 mg/cm.sup.2 of polymer were applied.

(19) Eudragit L 30D-55 Control and Outer Coating:

(20) 10% TEC (based on polymer weight) was dissolved in water, and added into Eudragit L 30D-55 dispersion. 50% talc based on polymer weight was homogenized in water and added into above dispersion. The total solid content of the coating dispersion was 20%. 5 mg/cm.sup.2 of polymer was applied.

(21) HP-55 Coating (Hydroxypropyl Methylcellulose Phthalate)

(22) 6% HP-55 solution was prepared by dissolving in ethonal/water (80:20). 5 mg/cm.sup.2 of polymer was applied.

(23) 4.2 Coating Conditions

(24) Table 2 summarizes the coating conditions for prednisolone tablets and table 3 summarizes the coating conditions for prednisolone pellets.

(25) Table 2 Shows the Coating Conditions for Prednisolone Tablets.

(26) TABLE-US-00002 Inlet Outlet Atomizing Flow temperature temperature Capacity pressure rate Formulations ( C.) ( C.) of fan (bar) (ml/min) L 30D-55, organic acid 40 30 15 0.2 0.5-1.5 inner coat L100/S100/FS inner 40 30 15 0.2 1.5 coat HPMC E5 subcoating 40 30 15 0.2 1.5 L 30D-55 control and 40 30 15 0.2 2.0 outer coating HP-55 coating 45 35 15 0.2 2.0
Table 3 shows the coating conditions for prednisolone pellets.

(27) TABLE-US-00003 Inlet Outlet Atomizing Flow temperature temperature Capacity pressure rate Formulations ( C.) ( C.) of fan (bar) (ml/min) L 30D-55, organic acid 40 30 15 0.6 1.5 inner coating HPMC subcoating 45 35 15 2.0 1.5 L 30D-55 control and 40 30 15 0.6 2 outer coating
5. Coating for Theophylline Pellets

(28) Theophylline pellets were coated in fluid bed (Huettlin Mycrolab).

(29) 5.1 Coating Formulations

(30) Eudragit L 30D-55 with 10% Citric Acid Inner Coating:

(31) 10% citric acid (based on polymer weight), 5% triethylcitrate (TEC) (based on polymer weight) were dissolved in water, and added into EUDRAGIT L30 D-55 dispersions. The above dispersions were then neutralised to pH 5.6 using 1 M NaOH and the dispersions turned to clear solutions. 50% Talc based on polymer weight was homogenised in water and added to above solution. The total solid content of the coating dispersion was 10%. 5 mg/cm.sup.2 of polymer was applied.

(32) Eudragit L 30D-55 Control and Outer Coating:

(33) 10% TEC (based on polymer weight) was dissolved in water, and added into Eudragit L 30 D-55 dispersion. 50% talc based on polymer weight was homogenized in water and added into above dispersion. The total solid content of the coating dispersion was 20%. 5 mg/cm.sup.2 of polymer was applied.

(34) 4.2 Coating Conditions

(35) Eudragit L 30D-55 with 10% Citric Acid Inner Coating:

(36) Inlet air temperature: 38.0-40.0 C.; product temperature: 28-30 C.; Exhaust air temperature: 27-29 C.; exhaust air humidity: 25-38%; micro climate: 0.6 bar; airflow: 20.0 m.sup.3/h; atomizing air pressure: 1.6-2.3 bar; spray rate: 2.2 g/min.

(37) Eudragit L 30D-55 Control and Outer Coating:

(38) Inlet air temperature: 40.0-45.0 C.; product temperature: 28-30 C.; Exhaust air temperature: 22-27 C.; exhaust air humidity: 40-45%; micro climate: 0.4 bar; airflow: 16.0-18.0 m.sup.3/h; atomizing air pressure: 0.6-0.8 bar; spray rate: 2.2 g/min.

(39) 6. Dissolution Tests for Eudragit Coated Tablets and Pellets, Comprising as Active Ingredient Prednisolone or Theophylline, Respectively

(40) Dissolution test for coated tablets and pellets comprising as active ingredient prednisolone or theophylline, respectively, were carried out using BP Method II paddle apparatus (Model PTWS, Pharmatest, Hainburg, Germany). The volume of the dissolution media was 900 ml maintained at 370.5 C. and a paddle speed of 50 rpm was employed. The amount of prednisolone or theophylline released from the coated tablets or pellets was determined by UV spectrophotometer at 247 nm for prednisolone or at 271 nm for theophylline, respectively. Tablets or pellets were placed for 120 min into 0.1N HCl, and subsequently into different pH of phosphate buffer.

Example 1

Effects of Different Acid Concentrations in the Inner Coat on Drug Release from Double Coating System

(41) The present example shows the effects of different adipic acid concentration in the inner coat (pH 5.6) on the drug release. For this experiment the following prednisolone-containing tablets were used: i) control tablets containing Eudragit L 30D-55, 5 mg/cm.sup.2; ii) double-coated tablets comprising outer coating Eudragit L 30D-55, 5 mg/cm.sup.2, inner coating of Eudragit L 30D-55, 5 mg/cm.sup.2, 10, 15 and 20% by weight adipic acid, respectively, pH 5.6. The tablets were subjected to a solution of 0.1 N HCl for 2 h and subsequently to a phosphate buffer pH 5.6.

(42) The drug release rate was strongly increased when using adipic acid concentration in the inner coat of 10%, 15% and 20% by weight compared to the control solid dosage form having the same outer coating but which does not comprise an inner coating (data not shown). Further, it was observed that the coating process using Eudragit L 30D-55 neutralised to pH 5.6 further comprising adipic acid as the inner coat was easy, and the higher the adipic acid concentration, the easier was the coating process.

(43) Further experiments were carried out with the following prednisolone-containing tablets: i) control tablets containing Eudragit L 30D-55, 5 mg/cm.sup.2; ii) double-coated tablets comprising outer coating Eudragit L 30D-55, 5 mg/cm.sup.2, inner coating of Eudragit L 30D-55, 10, 15, 20 and 30% by weight citric acid, respectively, pH 5.6. The tablets were subjected to a solution of 0.1 N HCl for 2 h and subsequently to a phosphate buffer pH 5.6.

(44) Table 4 summarizes a comparison of different citric acid concentrations in the inner coat. The drug releases from 10% by weight citric acid double coated tablets were faster than from 10% adipic acid double coated tablets (s. table 5). In pH 5.6 buffer, the drug release differences of 10, 15, 20, 30% citric acid formulations were very small.

(45) In buffer having pH 5.5 15% the citric acid formulation showed faster drug release than 10% citric acid (data not shown).

(46) Table 4 shows the dissolution profiles of citric acid-containing Eudragit L 30D-55 double coated prednisolone tablets in 0.1N HCl for 2 h and subsequent pH 5.6 phosphate buffer (all the formulations have the same outer coat: Eudragit L30D-55, 5 mg/cm.sup.2).

(47) TABLE-US-00004 outer coating: outer coating: outer coating: outer coating: EudragitL30D-55 EudragitL30D-55 EudragitL30D-55 EudragitL30D-55 Control: inner coating: inner coating: inner coating: inner coating: EudragitL30D-55 EudragitL30D-55 EudragitL30D-55 EudragitL30D-55 EudragitL30D-55; time enteric coating; 10% by weight 15% by weight 20% by weight 30% by weight [min] no inner coating citric acid, pH 5.6 citric acid, pH 5.6 citric acid, pH 5.6 citric acid, pH 5.6 120 0.0 0.0 0.0 0.0 0.0 150 0.0 0.5 1.1 1.1 2.4 155 0.0 1.0 2.0 4.9 7.8 160 0.0 2.8 5.5 6.9 17.3 165 0.0 7.1 14.1 9.0 21.1 170 0.0 12.7 24.7 13.2 26.3 180 0.0 32.9 48.8 63.1 34.8 195 0.0 62.8 72.0 87.0 41.0 240 1.1 103.8 94.0 94.6 89.2 375 10.0 106.8 97.1 99.3 98.1

Example 2

Effects of Different Amounts of Outer Coat

(48) In this experiment the effects of application of different amounts of outer coating on the dissolution was investigated. For this experiment the following prednisolone-containing tablets were used: i) control tablets containing Eudragit L 30D-55, 3, 4 and 5 mg/cm.sup.2, respectively; ii) double-coated tablets comprising outer coating Eudragit L 30D-55, 3, 4 and 5 mg/cm.sup.2, respectively; inner coating of Eudragit L 30D-55, 20% by weight citric acid, pH 5.6. The tablets were subjected to a solution of 0.1 N HCl for 2 h and subsequently to a phosphate buffer pH 5.6.

(49) It was shown that the dissolution rate of an outer coating of 5 mg/cm.sup.2 (30% release was achieved within 175 min, 50% release was achieved within 180 min) was higher than that of 4 mg/cm.sup.2 (30% release within 175 min, 50% release within 220 min), which again was higher than that of 3 mg/cm.sup.2 outer coat (30% release within 340 min), compared to the controls (not having an inner coating): 5 mg/cm.sup.2 outer coating: 50% release was achieved within 530 min; 4 mg/cm.sup.2 outer coating: 50% release within 415 min; 3 mg/cm.sup.2 outer coating: 50% release within 275 min.

(50) Further experiments were carried out using the following prednisolone-containing tablets: i) control tablets containing Eudragit L 30D-55, 3, 4 and 5 mg/cm.sup.2, respectively; ii) double-coated tablets comprising outer coating Eudragit L 30D-55, 3, 4 and 5 mg/cm.sup.2, respectively; inner coating of Eudragit L 30D-55, 10% by weight adipic acid, pH 5.6. The tablets were subjected to a solution of 0.1 N HCl for 2 h and subsequently to a phosphate buffer pH 5.6. Table 5 shows the results of the dissolution of double coated tablets for 10% adipic acid formulation.

(51) Table 5 shows the dissolution profiles of 10% adipic acid-containing Eudragit L 30D-55 double coated prednisolone tablets in 0.1N HCl for 2 h and subsequent pH 5.6 phosphate buffer (all the formulations have the same outer coat: EudragitL30D-55, 5 mg/cm.sup.2).

(52) TABLE-US-00005 outer coating: outer coating: outer coating: EudragitL30D-55 EudragitL30D-55 EudragitL30D-55 5 mg/cm.sup.2 4 mg/cm.sup.2 3 mg/cm.sup.2 Control: Control: Control: inner coating: inner coating: inner coating: coating: coating: coating: EudragitL30D-55; EudragitL30D-55; EudragitL30D-55; time EudragitL30D-55 EudragitL30D-55 EudragitL30D-55 10% adipic acid, 10% adipic acid, 10% adipic acid, [min] 5 mg/cm.sup.2 4 mg/cm.sup.2 3 mg/cm.sup.2 pH 5.6, 5 mg/cm.sup.2 pH 5.6, 5 mg/cm.sup.2 pH 5.6, 5 mg/cm.sup.2 120 0.0 0.0 0.0 0.0 0.0 0.0 165 0.0 0.0 0.4 0.6 11.9 4.5 180 0.0 0.0 1.3 2.2 36.1 7.1 200 0.2 0.5 3.6 29.9 67.7 10.0

Example 3

Effects of the Degree of Neutralization of the Inner Coating Solution

(53) In this experiment the effects of the degree of neutralisation of the inner coating solution on the drug release profiles was investigated. For this test double coated tablets with an inner coating of Eudragit L30D-55 comprising 10% by weight citric acid is used. In detail: for this experiment the following prednisolone-containing tablets were used: i) control tablets containing Eudragit L 30D-55, 5 mg/cm.sup.2; ii) double-coated tablets comprising outer coating Eudragit L 30D-55, 5 mg/cm.sup.2; inner coating of Eudragit L 30D-55, 10% by weight citric acid, pH 5.6, 5.8 and 6.0, respectively, 5 mg/cm.sup.2. The tablets were subjected to a solution of 0.1 N HCl for 2 h and subsequently to a phosphate buffer pH 5.6.

(54) The experiment shows a slight increase of drug release when the pH of inner coating solution was increased from pH 5.6 to pH 5.8. When neutralizing the inner coating solution to pH 6.0 the drug release rate was further significantly increased (see table 6). Here, the lag time of drug release in pH 5.6 phosphate buffer was reduced from 40 min to 5 min.

(55) Table 6 shows the dissolution profiles of 10% citric acid-containing Eudragit L 30D-55 double coated prednisolone tablets with different neutralisation values in 0.1N HCl for 2 h and subsequent pH 5.6 phosphate buffer (all the formulations have the same outer coat: EudragitL30D-55, 5 mg/cm.sup.2)

(56) TABLE-US-00006 outer coating: outer coating: outer coating: EudragitL30D-55 EudragitL30D-55 EudragitL30D-55 Control: inner coating: inner coating: inner coating: Coating: EudragitL30D-55; EudragitL30D-55; EudragitL30D-55; time EudragitL30D-55 10% by weight 10% by weight 10% by weight [min] 5 mg/cm.sup.2 citric acid, pH 5.6 citric acid, pH 5.8 citric acid, pH 6.0 120 0.0 0.0 0.0 0.0 135 0.0 0.0 0.0 9.9 160 0.0 2.8 12.9 57.4 170 0.0 12.7 24.8 78.2 190 0.0 52.1 60.3 92.4 375 10.0 106.3 96.0 94.9 535 50.0 n.d. n.d. n.d.

Example 4

Effects on the Drug Release Using Eudragit L 100 as Inner Coat

(57) For investigating the influence of the type of polymer on the drug release Eudragit L 100 was used as inner coating solution which was neutralised to pH 6.2. For this experiment the following prednisolone-containing tablets were used: i) control tablets containing Eudragit L 30D-55, 5 mg/cm.sup.2; ii) double-coated tablets comprising outer coating Eudragit L 30D-55, 5 mg/cm.sup.2; inner coating of Eudragit L100, 10% by weight citric acid, pH 6.2, 5 mg/cm.sup.2. The tablets were subjected to a solution of 0.1 N HCl for 2 h and subsequently to a phosphate buffer pH 5.6.

(58) As result it was observed that drug release from double coated tablets with Eudragit L 100 and 10% by weight citric acid as inner coating showed very fast drug release profile, with only 5 min lag time (10% drug release within 145 min, 50% drug release within 170 min), which was much faster than control Eudragit L 30D-55 coating (10% drug release within 370 min, 50% drug release within 530 min).

(59) Further, different neutralisation values of Eudragit L 100 as pH 6.2 and pH 6.8 were compared. For this experiment the following prednisolone-containing tablets were used: i) control tablets containing Eudragit L 30D-55, 5 mg/cm.sup.2; ii) double-coated tablets comprising outer coating Eudragit L 30D-55, 5 mg/cm.sup.2; inner coating of Eudragit L100, 10% by weight citric acid, pH 6.2 and 6.8, respectively, 5 mg/cm.sup.2; iii) double-coated tablets comprising outer coating Eudragit L 30D-55, 5 mg/cm.sup.2; inner coating of Eudragit L100, 15% by weight adipic acid, pH 6.8, 5 mg/cm.sup.2; iv) double-coated tablets comprising outer coating Eudragit L 30D-55, 5 mg/cm.sup.2; inner coating of Eudragit L30D-55, 10% by weight citric acid, pH 5.6 and 6.0, respectively, 5 mg/cm.sup.2. The tablets were subjected to a solution of 0.1 N HCl for 2 h and subsequently to a phosphate buffer pH 5.6.

(60) Different neutralisation values of Eudragit L 100 as pH 6.2 and pH 6.8 were compared and drug release profiles at these two neutralisation values showed no differences (Table 7). Comparing to the double coating formulation with Eudragit L 30D-55 as inner coat at pH 6.0 neutralisation level, drug release from Eudragit L 100 with 10% citric acid double coated tablets had the same lag time (5 min), but showed slightly slower slope of release profile. Inner coat formulation with Eudragit L 100 and 15% adipic acid was also investigated, and showed very fast drug release, with 5 min lag time and release slope similar to Eudragit L 30D-55, pH 6.0 formulation.

(61) TABLE-US-00007 TABLE 7 Dissolution profiles of Eudragit L 30D-55, L100 double coated prednisolone tablets in 0.1N HCl for 2 h and subsequent pH 5.6 phosphate buffer (all the formulations have the same outer coat: Eudragit L 30D-55, 5 mg/cm.sup.2) outer coating: outer coating: outer coating: outer coating: outer coating: EudragitL30D-55 EudragitL30D-55 EudragitL30D-55 EudragitL30D-55 EudragitL30D-55 Control: inner coating: inner coating: inner coating: inner coating: inner coating: coating: EudragitL100, EudragitL100, EudragitL30D-55; EudragitL30D-55; EudragitL100; time EudragitL30D-55 10% citric acid, 10% citric acid, 10% citric acid, 10% citric acid, 10% adipic acid, [min] 5 mg/cm.sup.2 pH 6.2 pH 6.8 pH 6.0 pH 5.6 pH 6.8 120 0.0 0.3 0.0 0.0 0.0 0.0 135 0.0 3.9 4.2 9.9 0.0 8.3 150 0.0 18.3 19.1 36.0 0.5 30.6 170 0.0 49.7 55.2 78.2 12.7 67.7 190 0.0 83.1 81.1 92.4 52.1 88.2 375 10.0 96.1 94.5 94.9 106.8 92.6

Example 5

Acid Resistance Tests for Double Coated Prednisolone Tablets

(62) In this experiment the acid resistance of double coated prednisolone tablets was studied. For this experiment the following prednisolone-containing tablets were used: i) control tablets containing Eudragit L 30D-55, 5 mg/cm.sup.2; ii) double-coated tablets comprising outer coating Eudragit L 30D-55, 5 mg/cm.sup.2; inner coating of Eudragit L30D-55, 10% by weight adipic acid, pH 5.6, 5 mg/cm.sup.2. The tablets were subjected to 0.1 N HCl solutions of different pH. As result is was shown that there is no drug release in 0.1 N HCl for 21 h, and also no drug release in HCl solution for 3 h having pH 2.0, 3.0 and 4.0, respectively. These results indicate that the double coating system has good acid resistance (data not shown).

Example 6

Comparison of Drug Release from Double Coated Prednisolone Tablets Comprising Either Citric Acid or Adipic Acid

(63) In this experiment the influence of the type of organic acid is investigated. For this experiment the following prednisolone-containing tablets were used: i) control tablets containing Eudragit L 30D-55, 5 mg/cm.sup.2; ii) double-coated tablets comprising outer coating Eudragit L 30D-55, 5 mg/cm.sup.2; inner coating of Eudragit L30D-55, 10% by weight adipic acid or citric acid, respectively, pH 5.6, 5 mg/cm.sup.2.

(64) Table 8 shows the comparison of drug release from double coated and control coated prednisolone tablets at pH 5.6 phosphate buffer after 2 h in 0.1 N HCl. All the inner coat of the double coated formulations were neutralized to pH 5.6.

(65) In particular the drug released from 10% citric acid and 10% adipic acid double coated tablets in pH 5.5, 5.6 and 5.8 buffer were tested (table 8 only shows the double coated tablets in pH 5.6 buffer). In all of the test pH values, double coated tablets containing an organic acid (either citric acid or adipic acid) showed faster drug release than control coated tablets. In all of these three pH values, 10% citric acid formulation showed faster drug release rates than 10% adipic acid formulation.

(66) TABLE-US-00008 TABLE 8 Drug release profiles of Eudragit L 30D-55 double coated and control coated prednisolone tablets in 0.1N HCl for 2 h and subsequent pH 5.6 phosphate buffer: all the double coated formulations have the same outer coat: EudragitL30D-55, 5 mg/cm.sup.2 outer coating: outer coating: Control: EudragitL30D-55 EudragitL30D-55 coating: inner coating: inner coating: time EudragitL30D-55 EudragitL30D-55, EudragitL30D-55, [min] 5 mg/cm.sup.2 10% adipic acid, pH 5.6 10% citric acid, pH 5.6 120 0.0 0.0 0.0 155 0.0 0.0 1.0 170 0.0 1.0 12.7 190 0.0 6.7 52.1 200 0.2 29.9 71.9 235 1.0 93.3 102.8 375 10.0 103.0 106.8

Example 7

Drug Release Studies with Theophylline Pellets; Comparison

(67) The present example shows the effects of double coating on theophylline pellets. For this experiment the following theophylline-containing pellets were used: i) control pellets containing Eudragit L30D-55, 5 mg/cm.sup.2, ii) double coated pellets comprising outer coating Eudragit L30D-55, 5 mg/cm.sup.2, inner coating of Eudragit L30D-55, 10% citric acid, pH 5.6.

(68) In this experiment the acid resistance of double coated theophylline pellets was tested. It was shown that the use of a different active ingredient, theophylline, that there was no drug release from double coated pellets in 0.1 N HCl for 2 h, which indicates that the double coating formulation has good acid resistance.

(69) Further tests refer to the drug release from double coated and control coated theophylline pellets at pH 5.0 and 5.5, phosphate buffer after 2 h in 0.1 N HCl. There was very slow drug release from control coated pellets at pH 5.5, and no drug release from these pellets at pH 5.0. However, for double coated pellets, drug releases already started at pH 5.0 and showed fast and complete drug release at pH 5.5.

Example 8

Coating Dissolution Process for Double Coated, HPMC Inner coating (subcoated) and control coated prednisolone pellets

(70) For this experiment the following prednisolone-containing pellets were used: i) control pellets containing Eudragit L 30D-55, 5 mg/cm.sup.2; ii) double-coated pellets comprising outer coating Eudragit L 30D-55, 5 mg/cm.sup.2, inner coating of Eudragit L 30D-55, 15% by weight adipic acid, pH 5.6, 5 mg/cm.sup.2; iii) HPMC subcoated pellets containing outer coating Eudragit L 30D-55, 5 mg/cm.sup.2, inner coating HPMC pH 7.0, 3 mg/cm.sup.2.

(71) As result is was observed that there were no drug release from both 15% adipic acid double-coated pellets and control Eudragit L 30D-55 coated pellets in 0.1 M HCl for 2 h. However, in subsequent pH 5.5 buffer, prednisolone release from 15% adipic acid double-coated pellets was much faster than control coated pellets, with lag time 40 min and 105 min respectively.

(72) Double-coated pellets with HPMC E5 (hydroxypropyl methylcellulose) 3 mg/cm.sup.2 as a subcoat (inner coating) were also investigated. The lag time for drug release from HPMC-subcoated pellets was reduced to 90 min, 15 min faster than the control coated pellets (data not shown).

Example 9

Drug Release of Tablets Comprising Inner Coating with Only Neutralization without Organic Acid

(73) For this experiment the following prednisolone-containing tablets were used: i) control tablets containing Eudragit L 30D-55, 5 mg/cm.sup.2; ii) double-coated tablets comprising outer coating Eudragit L 30D-55, 5 mg/cm.sup.2, inner coating of Eudragit L 30D-55 (5 mg/cm.sup.2), 10% citric acid, pH 5.6 or 6.0, respectively; iii) double-coated pellets comprising outer coating Eudragit L 30D-55, 5 mg/cm.sup.2, inner coating of Eudragit L 30D-55 (5 mg/cm.sup.2), pH 5.8 or 6.0, respectively. If neutralizing the inner coat to pH 5.8 and pH 6.0 without adding organic acid, the double coated tablets still showed faster drug release than the control. However the inventive formulations with 10% citric acid showed even faster drug release at comparable pH values of 5.8 or 6.0, respectively (table 9). These results clearly show that without the addition of organic acids the mere higher neutralization degree of the inner coating compared to the outer coating a dramatic increase in the drug release rate is achieved, however the drug release rate is not as good as for formulations which include organic acids in the inner coating.

(74) TABLE-US-00009 TABLE 9 Dissolution profiles of Eudragit L 30D-55 double coated prednisolone tablets with or without citric acid in 0.1N HCl for 2 h and subsequent pH 5.6 phosphate buffer (all the formulations have the same outer coat: EudragitL30D-55, 5 mg/cm.sup.2) outer coating: outer coating: outer coating: outer coating: Control: EudragitL30D-55 EudragitL30D-55 EudragitL30D-55 EudragitL30D-55 coating: inner coating: inner coating: inner coating: inner coating: time EudragitL30D-55 EudragitL30D-55, EudragitL30D-55, EudragitL30D-55, EudragitL30D-55, [min] 5 mg/cm.sup.2 10% citric acid, pH 5.8 10% citric acid, pH 6.0 pH 5.8 (no addition of acid) pH 6.0 (no addition of acid) 120 0.0 0.0 0.0 0.0 0.0 125 0.0 0.0 0.4 0.0 0.0 140 0.0 1.4 17.4 0.0 1.7 155 0.0 8.7 46.5 0.5 11.6 170 0.0 24.9 78.3 5.1 30.2 180 0.0 43.1 89.1 14.9 45.4 190 0.0 60.4 92.4 26.6 59.4 210 0.2 83.3 93.7 53.6 80.5 375 10.0 96.0 94.9 95.1 90.4

Example 10

Drug Release of Double Coated Tablets Comprising Inner Coating with Organic Acid but without Neutralization

(75) For this experiment the following prednisolone-containing tablets were used: i) control tablets containing Eudragit L 30D-55, 5 mg/cm.sup.2; ii) double-coated tablets comprising outer coating Eudragit L 30D-55, 5 mg/cm.sup.2, inner coating of Eudragit L 30D-55, 20% citric acid, pH 5.6, 5 mg/cm.sup.2; iii) double-coated tablets comprising outer coating Eudragit L 30D-55, 5 mg/cm.sup.2, inner coating of Eudragit L 30D-55, 20% by weight citric acid, non-neutralized, 5 mg/cm.sup.2. Double coated tablets with inner coat having 20% citric acid, but non-neutralized, showed no drug release in pH 5.6 phosphate buffer for 12 h (table 10 shows up to 6 hours). Assumingly, the acidity of citric acid in the inner coat decreased the microenvironment pH of Eudragit L 30D-55 outer coat, thus decreased the coat dissolution speed.

(76) TABLE-US-00010 TABLE 10 Dissolution profiles of Eudragit L 30D-55 double coated prednisolone tablets with or without neutralization in 0.1N HCl for 2 h and subsequent pH 5.6 phosphate buffer (all the formulations have the same outer coat: EudragitL30D-55, 5 mg/cm.sup.2) outer coating: outer coating: Control: EudragitL30D-55 EudragitL30D-55 coating: inner coating: inner coating: time EudragitL30D-55 EudragitL30D-55, EudragitL30D-55; [min] 5 mg/cm.sup.2 20% citric acid, pH 5.6 20% citric acid, non-neutralized 120 0.0 0.0 0.0 165 0.0 9.0 0.2 170 0.0 13.2 0.1 175 0.0 31.4 0.0 185 0.0 77.1 0.0 195 0.0 87.0 1.4 300 5.2 97.7 0.5 375 10.0 99.3 0.7

Example 11

Drug Release of Double Coated Tablets Comprising HPMC as Inner Coating

(77) For this experiment the following prednisolone-containing tablets were used: i) control tablets containing Eudragit L 30D-55, 5 mg/cm.sup.2; ii) double-coated tablets comprising outer coating Eudragit L 30D-55, 5 mg/cm.sup.2, inner coating of Eudragit L 30D-55, 20% citric acid, pH 5.6, 5 mg/cm.sup.2; iii) double-coated tablets comprising outer coating Eudragit L 30D-55, 5 mg/cm.sup.2, inner coating of HPMC E-5, using 1, 3 and 5 mg/cm.sup.2, respectively, pH 7.0.

(78) The tablets were subjected to 0.1N HCl for 2 h and subsequently to pH 5.6 phosphate buffer. The dissolution rates for 1 mg/cm.sup.2 and 3 mg/cm.sup.2 HPMC E5 inner coated tablets were faster than control coat (data not shown). The fastest drug release was found with HPMC E5 inner coat amount at 3 mg/cm.sup.2, but still slower than Eudragit L 30D-55, 20% citric acid, pH 5.6 inner coated formulation.

(79) Further experiments were carried out with the following prednisolone-containing tablets: i) control tablets containing Eudragit L 30D-55, 5 mg/cm.sup.2; ii) double-coated tablets comprising outer coating Eudragit L 30D-55, 5 mg/cm.sup.2, inner coating of Eudragit L 30D-55, 10% citric acid, pH 5.6 and 6.0, respectively, 5 mg/cm.sup.2; iii) double-coated tablets comprising outer coating Eudragit L 30D-55, 5 mg/cm.sup.2, inner coating of HPMC E 5, 5 mg/cm.sup.2, with either a) 10% citric acid which was completely neutralized or b) 10% Na citrate or c) 10% NaCl, respectively, each having pH 7.0.

(80) As summarized in table 11, the tablets comprising 10% NaCl, Na citrate and citric acid (with equal Mole of NaOH to completely neutralized) included in the HPMC E5 inner coat formulation showed fast drug release profiles (table 11). The HPMC E5 with 10% salt formulations still showed slower drug release comparing to Eudragit L 30D-55, 10% citric acid, pH 6.0 inner coat formulation.

(81) TABLE-US-00011 TABLE 11 Dissolution profiles of Eudragit L 30D-55 double coated prednisolone tablets with HPMC E5 as inner coat in 0.1N HCl for 2 h and subsequent pH 5.6 phosphate buffer (all the formulations have the same outer coat: EudragitL30D-55, 5 mg/cm.sup.2) outer coating: outer coating: outer coating: outer coating: outer coating: EudragitL30D-55 EudragitL30D-55 EudragitL30D-55 EudragitL30D-55 EudragitL30D-55 Control: inner coating: HPMC; inner coating: HPMC; inner coating: HPMC; inner coating: inner coating: EudragitL30D-55 10% citric acid, 10% Na citrate, 10% NaCl, EudragitL30D-55, EudragitL30D-55; time enteric coating; completely neutralized without without 10% citric acid 10% citric acid, [min] no inner coating with NaOH; neutralization neutralization pH 5.6 pH 6.0 120 0.0 0.0 0.0 0.0 0.0 0.0 135 0.0 0.0 0.0 0.0 0.0 9.9 145 0.0 0.2 0.1 0.0 0.3 25.8 155 0.0 0.3 0.6 0.0 1.0 46.4 170 0.0 5.7 7.5 0.0 12.7 78.2 175 0.0 10.0 10.1 2.2 22.6 85.1 185 0.0 22.3 18.4 14.1 42.4 91.3 195 0.0 37.7 29.5 33.4 62.8 92.9 200 0.2 48.3 34.5 45.0 71.9 93.2 215 0.3 75.1 52.8 71.6 90.4 93.4

Example 12

Drug Release of Double Coated Tablets Comprising HP-55 (Hydroxypropyl Methylcellulose Phthalate) as Outer Coating

(82) For this experiment the following prednisolone-containing tablets were used: i) control tablets containing Eudragit L 30D-55, 5 mg/cm.sup.2; ii) double-coated tablets comprising outer coating Eudragit L 30D-55, 5 mg/cm.sup.2, inner coating of Eudragit L 30D-55, 10% citric acid, pH 5.6, 5 mg/cm.sup.2; iii) HP-55 coated tablets, 5 mg/cm.sup.2; iv) double-coated tablets comprising outer coating HP-55, 5 mg/cm.sup.2, inner coating of Eudragit L 30D-55, 10% citric acid, pH 5.6, 5 mg/cm.sup.2. The tablets were subjected to 0.1N HCl for 2 h and subsequently to pH 5.6 phosphate buffer.

(83) Enteric coated prednisolone tablets with HP-55 (hydroxypropyl methylcellulose phthalate, which is an anionic polymer) as coating polymer showed much faster drug release than Eudragit L 30D-55 with same amount of polymer applied (5 mg/cm.sup.2). There was no drug release from HP-55 coated tablets in 0.1 N HCl for 2 h. In subsequent pH 5.6 phosphate buffer, there was almost no drug release lag time for HP-55 coating. The drug release profiles for HP-55 coating showed two phases in pH 5.6 phosphate buffer. Drug release was slow in the first 20 min, and became very fast after that. HP-55 outer coating with Eudragit L 30D-55, 10% citric acid, pH 5.6 formulation as inner coat showed further improvement of drug release. These results are summarized in table 12.

(84) TABLE-US-00012 TABLE 12 Comparison of drug release from Eudragit L 30D-55 coating and HP-55 coating in 0.1N HCl for 2 h and subsequent pH 5.6 phosphate buffer outer coating: outer coating: Control: EudragitL30D-55 HP-55 EudragitL30D-55 inner coating: inner coating: time enteric coating; EudragitL30D-55; HP-55 coated EudragitL30D-55; [min] no inner coating 10% citric acid, pH 5.6 no inner coating 10% citric acid, pH 5.6 120 0.0 0.0 0.0 0.0 135 0.0 0.0 2.2 5.6 145 0.0 0.3 4.0 10.6 165 0.0 7.1 10.5 36.0 180 0.0 32.9 28.1 57.8 175 0.0 22.6 20.7 50.4 180 0.0 32.9 28.1 57.8 190 0.0 52.1 42.7 70.1

Example 13

Drug Release of Double Coated Tablets Comprising 10% Citric Acid, 10% Na Citrate and 20% NaCl, Respectively as Inner Coating

(85) For this experiment the following prednisolone-containing tablets were used: i) control tablets containing Eudragit L 30D-55, 5 mg/cm.sup.2; ii) double-coated tablets comprising outer coating Eudragit L 30D-55, 5 mg/cm.sup.2, inner coating of Eudragit L 30D-55, 10% citric acid, pH 5.6, 5 mg/cm.sup.2; iii) double-coated tablets comprising outer coating Eudragit L 30D-55, 5 mg/cm.sup.2, inner coating of Eudragit L 30D-55, 10% citric acid, pH 6.0, 5 mg/cm.sup.2, iv) double-coated tablets comprising outer coating Eudragit L 30D-55, 5 mg/cm.sup.2, inner coating of Eudragit L 30D-55, 10% Na citrate, pH 6.0, 5 mg/cm.sup.2; v) double-coated tablets comprising outer coating Eudragit L 30D-55, 5 mg/cm.sup.2, inner coating of Eudragit L 30D-55, 20% by weight NaCl, pH 5.6, 5 mg/cm.sup.2. The tablets were subjected to 0.1N HCl for 2 h and subsequently to pH 5.6 phosphate buffer.

(86) Table 13 shows the drug release profile of double coated prednisolone tablets with 10% by weight Na citrate in the inner coat and neutralized to pH 6.0. Compared to the 10% citric acid formulation (also neutralized to pH 6.0, drug release from the 10% Na citrate formulation was slower.

(87) The double coated tablet having an inner coat formulation with 20% NaCl and also neutralized to pH 5.6 showed a drug release which was similar to the 10% citric acid pH 5.6 formulation (table 13).

(88) It was not possible to coat with NaCl-containing non-neutralized Eudragit L 30D-55 formulation. Eudragit L 30D-55 dispersion changed to semi-solid after adding NaCl into the dispersion. The sendimented particles redissolved until adding 1 M NaOH and neutralized to pH 5.6.

(89) TABLE-US-00013 TABLE 13 dissolution test of Eudragit L30D-55 double coated prednisolone tablets in 0.1N HCl for 2 h and subsequent pH 5.6 phosphate buffer (all formulations have the same outer coat: EudragitL30D-55, 5 mg/cm.sup.2). outer coating: outer coating: outer coating: outer coating: Control: EudragitL30D-55 EudragitL30D-55 EudragitL30D-55 EudragitL30D-55 EudragitL30D-55 inner coating: inner coating: inner coating: inner coating: Time enteric coating; EudragitL30D-55; EudragitL30D-55; EudragitL30D-55; Eudragit30D-55, [min] no inner coating 10% citric acid, pH 5.6 10% citric acid, pH 6.0 10% Na citrate, pH 6.0 20% NaCl, pH 5.6 120 0.0 0.0 0.0 0.0 0.0 135 0.0 0.0 9.9 0.5 0.0 150 0.0 0.5 36.0 5.6 0.0 160 0.0 2.8 57.4 16.1 0.2 170 0.0 12.7 78.2 34.0 11.6 180 0.0 32.9 89.1 53.6 27.2 190 0.0 52.1 92.4 72.5 43.2 375 10.0 106.8 94.9 n.d. 94.1