Acid resistant banding solution for acid resistant two piece hard capsules

Abstract

The present disclosure relates to acid resistant banding solutions for two piece hard capsules endowed with acid resistant properties, and methods of making and using acid resistant banding solutions. The present disclosure also relates, in part, to methods for banding such acid resistant capsules which provides an acid resistant seal between the capsule parts and achieves increased acid resistance in vitro.

Claims

1. A banded capsule dosage form comprising: a) an intrinsically acid resistant, two piece hard capsule comprising a body and a cap; b) the body and the cap being telescopically engaged to encapsulate an active agent; and c) an acid resistant band around the two piece hard capsule that seals a gap between the body and the cap, the acid resistant band comprising at least one acid resistant polymer selected from hydroxypropyl methylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), and mixtures thereof and wherein the acid resistant band is formed of a composition that is substantially free of an organic solvent; wherein the banded capsule dosage form provides improved resistance to acid media relative to a non-banded, closed capsule dosage form, as evaluated using a United States Pharmacopeia (USP) disintegration method (Chapter 701) in pH 1.2 media.

2. The banded capsule dosage form of claim 1 wherein the two piece hard capsule comprises HPMC, HPMCAS, or CAP.

3. The banded capsule dosage form according to claim 1, wherein the acid resistant band further comprises at least one alkaline compound selected from sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, tri sodium phosphate, sodium perborate, potassium hydroxide, lithium hydroxide, lithium carbonate, lithium bicarbonate, ammonium carbonate, ammonium bicarbonate, ammonium hydroxide, ammonia, and mixtures thereof.

4. The banded capsule dosage form according to claim 3 wherein the at least one alkaline compound is ammonia.

5. The banded capsule dosage form according to claim 1, wherein the acid resistant band further comprises at least one pharmaceutically acceptable or food acceptable plasticizer and/or coloring agent.

6. The banded capsule dosage form according to claim 1, wherein the at least one acid resistant polymer is HPMCP.

7. The banded capsule dosage form according to claim 1, wherein the at least one acid resistant polymer is CAP.

8. The banded capsule dosage form according to claim 1, wherein the at least one acid resistant polymer is HPMCAS.

9. The banded capsule dosage form according to claim 8, wherein the at least one acid resistant polymer is HPMCAS.

10. The banded capsule dosage form of claim 1, wherein the active agent is a pharmaceutical agent, a veterinary product, a food, or a dietary supplement.

11. A banded capsule dosage form comprising: a) an intrinsically acid resistant, two piece hard HPMC capsule comprising a body and a cap; b) the body and the cap being telescopically engaged to encapsulate an active agent; and c) an acid resistant band around the two piece hard capsule that seals a gap between the body and the cap, the acid resistant band comprising HPMCAS; wherein the banded capsule dosage form provides improved resistance to acid media relative to a non-banded, closed capsule dosage form, as evaluated using a United States Pharmacopeia (USP) disintegration method (Chapter 701) in pH 1.2 media.

12. The banded capsule dosage form according to claim 11, wherein the acid resistant band further comprises at least one alkaline compound selected from sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, tri sodium phosphate, sodium perborate, potassium hydroxide, lithium hydroxide, lithium carbonate, lithium bicarbonate, ammonium carbonate, ammonium bicarbonate, ammonium hydroxide, ammonia, and mixtures thereof.

13. The banded capsule dosage form according to claim 12, wherein the at least one alkaline compound is ammonia.

14. The banded capsule dosage form according to claim 11, wherein the acid resistant band further comprises at least one pharmaceutically acceptable or food acceptable plasticizer and/or coloring agent.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) The accompanying drawings, which are incorporated in and constitute a part of the specification, illustrate presently embodiments of the present disclosure, and together with the general description given above and the detailed description of the embodiments given below, serve to explain the principles of the present disclosure.

(2) FIG. 1 is a disintegration test at pH 1.2; and

(3) FIG. 2 is a dissolution test as a function of time.

DETAILED DESCRIPTION

(4) Accordingly, one aspect of the present disclosure provides acid resistant banding solutions for banding acid resistant two piece hard capsules, wherein said capsules comprise telescopically engaged capsule parts and are endowed with improved acid resistance properties compared to such capsules closed but without banding.

(5) In another aspect, the present disclosure provides an acid-resistant banding composition comprising an acid resistant polymer, at least one neutralizing compound such as an alkaline compound, and water as solvent.

(6) In another aspect, the present disclosure provides a method for banding two piece capsules which provides an acid resistant seal between the capsule parts and achieves an increased acid resistance in vitro.

(7) In a further aspect, the present disclosure relates to banding solutions for acid resistant capsules, and methods of banding acid resistant capsules with an acid resistant banding solution, which can be achieved without the use of organic solvents, and taking advantage of conventional banding techniques and equipment. See, e.g., F. Podczeck and B. Jones, Pharmaceutical Capsules, 2.sup.nd Ed., Pharmaceutical Press (2004), pp. 182-183.

(8) In one embodiment, a banding composition and method for banding acid resistant hard capsules is provided comprising at least one acid resistant polymer, at least one alkaline compound, and water.

(9) In another embodiment, the at least one acid resistant polymer in the banding composition for hard capsules is selected from the group consisting of methacrylic acid copolymers (copolymers of methacrylic acid and either methyl methacrylate or ethyl acrylate such as poly(methacrylic acid-co-ethyl acrylate) 1:1); cellulose acetate phthalate (CAP); cellulose acetate trimellitate (CAT); hydroxypropyl methylcellulose acetate succinate (HPMCAS); hydroxypropyl methylcellulose phthalate (HPMCP); carboxy methyl ethyl cellulose (CMEC); polyvinyl derivatives (e.g., polyvinyl acetate phthalate), and mixtures thereof.

(10) In another embodiment, the at least one alkaline compound of the banding composition is at least one compound selected from the group consisting of sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, tri sodium phosphate, sodium perborate, potassium hydroxide, lithium hydroxide, lithium carbonate, lithium bicarbonate, ammonium carbonate, ammonium bicarbonate, ammonium hydroxide, ammonia, and mixtures thereof.

(11) In one embodiment, the acid resistant banding composition is applied to, and therefore further comprises, an acid resistant capsule, and in another embodiment, the acid resistant banding composition is applied to and therefore further comprises a dip molded or injection molded hydroxypropylmethylcellulose (HPMC) acid resistant capsule. In other embodiments, the acid resistant banding composition is applied to, and therefore comprises, an enteric capsule such as a dip molded HPMCAS or CAP capsule.

(12) In one embodiment, the banding composition optionally further comprises at least one pharmaceutically acceptable or food acceptable plasticizer.

(13) In a further embodiment, the banding composition according to the present disclosure may further comprise at least one pharmaceutically acceptable or food acceptable coloring agent.

(14) The present disclosure also provides a method for the preparation of an acid resistant banding solution comprising: dispersing at least one acid resistant polymer in water under mixing; and adding at least one alkaline compound progressively under gentle stirring until the at least one acid resistant polymer is dissolved.

(15) In another embodiment, the method according to the present disclosure provides for the preparation of the banding solution carried out at room temperature. In another embodiment, the method according to the present disclosure provides for the use of the banding solution by banding hard capsules carried out at room temperature. Banding methods include automated and hand applied banding methods. See, e.g., Capsule Filling by D. K. Lightfoot, Tablets and Capsules Magazine, CSC Publishing (January 2007).

(16) In a further embodiment, the method for the preparation of an acid resistant banding solution further comprises adjusting the viscosity to a level appropriate for the hard capsule banding method. Non-limiting examples of appropriate viscosity for an acid resistant hard capsule banding solution and method are, for example, viscosities from about 50 cP to about 10,000 cP at room temperature; from about 100 cP to about 5000 cP; and from about 1500 cP to about 3100 cP. Desired viscosity is obtained by adjusting the concentration of the solution (i.e., by varying the amount of water and/or the amount of polymer).

(17) In other embodiments, the method for the preparation of an acid resistant banding solution further comprises adding to the solution at least one pharmaceutically acceptable or food acceptable plasticizer and/or at least one pharmaceutically acceptable or food acceptable coloring agent.

(18) Examples of pharmaceutically acceptable or food acceptable coloring agents include but are not limited to soluble dyes, including Tartrazine E102, FD&C Yellow 5D&C Yellow 10; Sunset Yellow E110, FD&C Yellow 6; D&C Red No. 22; D&C Red No. 28; D&C Red No. 33 (Acid Fushine); Allura Red E129, FD&C Red 40; Indigo carmine E132, FD&C Blue 2; Brilliant Blue FCF E133, FD&C Blue 1; Caramel, USP E150c; FD&C Green 3; FD&C red 3/Erythrosine; Azorubine; Brilliant Black; Chlorophyllin Copper Complex or sodium copper chlorophyllin; Ponceau 4R; Patent Blue V; Quinolone yellow; Curcumin, Red cabbage; and mixtures thereof. Other examples of pharmaceutically acceptable or food acceptable coloring agents include but are not limited to pigments, including Titanium Dioxide, Yellow Iron Oxide, Red Iron Oxide, Black Iron Oxide, Candurin silver fine, and mixtures thereof.

(19) The present disclosure also provides a method for banding an acid resistant hard capsule as described herein with an acid resistant banding composition comprising at least one acid resistant polymer, at least one alkaline compound, and water. The method includes determining the desired banding composition amount, measuring the banding composition required, and applying the banding composition to the acid resistant capsule.

(20) The present disclosure also provides an effective acid resistant banding of acid resistant hard capsules even with low band thickness or weight, such as lower than 10 mg, or even lower than 5 mg. These values are calculated based on the quantity, deposit, and concentration of the banding solution and results obtained for the dry band weight for size 0 capsules, and will be proportional for smaller capsules. The band weight is adapted as a function of the capsule size.

(21) The following non-limiting examples are offered to clarify the disclosure and are not intended to limit the scope of the present claims. The acid resistant capsules used in the banding examples are DRcaps capsules (HPMC) of size 0, natural transparent (N.T.) from CAPSUGEL, but any acid resistant capsule may be used. The banding solutions and methods according to the present disclosure can be applied to any size of DRcaps capsules or to any size of other acid resistant two piece capsules. The banding solution of the present disclosure can be applied to any two piece hard capsules with acid resistance performance, for example but without limitation, enteric capsules fabricated from hydroxypropylmethylcellulose acetate succinate (HPMCAS) or from cellulose acetate phthlalate CAP) may be banded using the banding solutions and methods according to the present disclosure.

EXAMPLES

(22) Three samples of banding solution were prepared using the HPMCP (HP-55), CAP, or HPMCAS respectively as acid resistant polymers. The alkaline compound used was an aqueous ammonia solution with a 35% NH.sub.3 concentration (ammonia solution 0.88 S.G. (35% NH.sub.3) from Fisher Scientific). The appropriate quantity by weight of polymer powder was first dispersed in the water at room temperature under stirring to obtain the desired weight ratio (see Table 1). Then the indicated amount of ammonia solution was added to the dispersion progressively under gentle stirring until the polymer particles were totally dissolved. A 0.1% solution of Patent Blue V-C.I. Food Blue 5 E131 (based on the polymer weight) was added to aid in the visualization of the banding. Table 1 presents the compositions and characteristics of the obtained banding solutions.

(23) TABLE-US-00001 TABLE 1 NH.sub.3 Viscosity Chemical Quantity Water Concentration (35%) (cPs) name Supplier Grade (g) (g) (%, w/w) (ml) at 22 C. pH HPMCP Shin-Etsu HP-55 100 400 20.0 17.5 1570 4.9 CAP Eastman CAP, 82.5 417.5 16.5 19.8 1959 7.4 NF HPMCAS Shin-Etsu Aquot 85 415 17.0 6.7 3012 5.5 AS-LG

(24) DRcaps capsules, size 0 were used for these banding tests. Capsules were first filled with a blend of lactose and FD&C Blue 2 or Acetyl paraminophenol (APAP) for visual disintegration testing or dissolution dosage testing, respectively.

(25) The band thickness or amount needed to provide an effective acid resistant banding was determined by the screening of the banding solution quantity applied on the capsule. The quantity of the banding solution applied on the capsules was determined by weighing the capsule before and immediately after the banding procedure and comparing the weights obtained. Banding was performed on a lab scale banding equipment from MG2 (Model SUM) with drying under room temperature conditions.

(26) The banded capsules were tested using the United States Pharmacopeia (USP) disintegration method (Chapter 701) in pH 1.2 media and evaluated by the visual approach. Accordingly, the sample capsules were filled with a blend of lactose and FD&C Blue 2. Table 2 summarizes the visual results of the test for the size 0 capsules.

(27) TABLE-US-00002 TABLE 2 Disintegration with disc at pH 1.2 USP/37 C. Sample size n = 6 capsules Approx. banding State at 30 min State at 1 hour solution # # Banding weight Shell Shell Polymer (mg) # Leaked # Emptied disintegration # Leaked # Emptied disintegration HP-55 25 0 0 0 0 0 0 20 0 0 0 0 0 0 15 0 0 0 1 0 0 10 0 0 0 1 0 0 CAP 25 0 0 0 0 0 0 20 0 0 0 0 0 0 15 0 0 0 0 0 0 10 0 0 0 0 0 0 HPMCAS 25 0 0 0 0 0 0 20 0 0 0 0 0 0 15 0 0 0 0 0 0 10 0 0 0 4 1 0

(28) The HP-55 banding solution was effective at about 20 mg or greater banding solution weight for size 0 capsules. The CAP banding solution was effective at all weights tested for size 0 capsules, i.e., about 10 mg or greater banding solution weight. The HPMCAS polymer banding solution was effective at about 15 mg or greater banding solution weight. Because the banding solution weight is proportional to the capsule size (i.e., diameter), these results for size 0 capsules (with a diameter of about 0.3 inches) may be extrapolated to smaller capsules, since smaller capsules would require less banding solution by weight.

(29) The banded capsules filled with APAP were tested using the USP disintegration method in pH 1.2 media and evaluated by the dosage approach, which measures the % of APAP dissolved after an hour disintegration test at pH 1.2. Table 3 and FIG. 1 summarize the results of the test.

(30) TABLE-US-00003 TABLE 3 DRCAPS Capsules, #0 1 hour disintegration test at pH 1.2/37 C. USP Banding type Closed HP-55 banding Banding 0 25 mg 20 mg 15 mg 10 mg quantity Tested N N = 3 N = 3 N = 3 N = 3 N = 3 N = 3 N = 3 N = 3 N = 3 N = 3 Observation Opened Opened Resistant 4/6 cap moved % APAP 97.7 92.6 6.2 8.4 8.0 7.4 8.4 6.9 6.3 7.7 dissolved AVG % APAP 95.2 7.3 7.7 7.7 7.0 Dissolved Banding type CAP banding Banding 25 mg 20 mg 15 mg 10 mg quantity Tested N N = 3 N = 3 N = 3 N = 3 N = 3 N = 3 N = 3 N = 3 Observation / Resistant % APAP 6.7 6.7 5.8 5.7 4.4 4.5 6.7 4.1 dissolved AVG % APAP 6.7 5.8 4.5 5.4 Dissolved Banding type HPMCAS banding Banding 25 mg 20 mg 15 mg 10 mg quantity Tested N N = 3 N = 3 N = 3 N = 3 N = 3 N = 3 N = 3 N = 3 Observation / Resistant 5/6 opened 1/6 cap moved % APAP 8.6 8.5 7.2 7.5 8.8 7.6 94.0 70.5 dissolved AVG % APAP 8.5 7.4 8.2 82.3 Dissolved

(31) Table 4 and FIG. 2 present the results obtained with the banded capsules filled with APAP by the dosage method assay (the APAP (acetaminophen) concentration in the dissolution media was measured with a UV spectrophotometer at a wavelength of 300 nm and compared to known concentration standards) in order to determine the % of APAP dissolved over a period of up to 240 minutes by the USP dissolution test (Chapter 711) and the Japanese Pharmacopoeia dissolution test (Chapter 9.41) methods. Six capsules were tested for each data point.

(32) TABLE-US-00004 TABLE 4 DRCAPS Capsules, #0 Banded with Banded with Banded with Time Closed HP-55 CAP HPMCAS Medium (min) % APAP dissolved pH1.2/37 C. 0 0.0 0.0 0.0 0.0 USP 15 0.7 0.4 0.7 0.4 30 2.1 0.9 1.0 1.1 45 4.1 1.5 1.2 1.8 60 6.1 2.4 1.6 2.7 75 8.1 3.3 2.0 3.8 90 10.0 4.3 2.5 4.8 105 12.1 5.5 3.0 5.9 120 14.8 6.7 3.4 7.1 (max: 18.2) (max: 8.1) (max: 8.1) (max: 8.1) pH6.8/37 C. 135 33.7 45.8 35.7 41.7 JP2 150 76.5 68.7 59.4 67.0 165 90.7 (min: 80.7 (min: 72.5) 74.7 (min: 81.1 (min: 72.8) 86.0) 72.1) 180 95.7 88.2 85.0 89.3 195 97.4 94.1 90.4 95.1 210 97.9 97.5 95.0 98.1 225 98.1 99.4 97.0 98.8

(33) All of the banding solutions tested were effective at retaining the acid resistance of a two piece HPMC hard capsule, and capsules with the banding solutions tested had greater acid resistance in in vitro testing compared with closed capsules without banding.

(34) In addition to DRCAP capsules, enteric capsules such as those fabricated from HPMCAS or from CAP can also be used with the methods according to the Examples and in banding tests such as the USP disintegration method described herein.

(35) Additional advantages and modifications will readily occur to those skilled in the art. Therefore, the present disclosure in its broader aspects is not limited to the specific details and representative embodiments shown and described herein. Accordingly, various modifications may be made without departing from the spirit or scope of the general inventive concept as defined by the appended claims and their equivalents.