Gastric reflux resistant dosage forms

Abstract

Gastric resistant film-forming compositions are described herein. The composition comprises a gastric resistant natural polymer, a film-forming natural polymer, and optionally a gelling agent. Suitable gastric resistant natural polymers include polysaccharides such as pectin and pectin-like polymers. The film-forming composition can be used to prepare soft or hard shell gelatin capsules which can encapsulate a liquid or semi-solid fill material or a solid tablet (Softlet) comprising an active agent and one or more pharmaceutically acceptable excipients. Alternatively, the composition can be administered as a liquid with an active agent dissolved or dispersed in the composition. The compositions are not only gastric resistant but may also prevent gastric reflux associated with odor causing liquids, such as fish oil or garlic oil, encapsulated in a unit dosage form and esophageal irritation due to the reflux of irritant drugs delivered orally.

Claims

1. An oral gastric resistant soft capsule shell comprising (a) about 2% to about 5% pectin by weight of the capsule shell; (b) about 25% to about 40% gelatin by weight of the capsule shell; and (c) less than about 2% by weight of the capsule shell of a gelling agent comprising calcium salts, magnesium salts, or calcium gelatin.

2. The shell of claim 1, wherein the gelling agent comprises less than about 1% by weight of the shell.

3. The shell of claim 1, further comprising one or more plasticizers comprising glycerol, sorbitol, sorbitans, maltitol, polyethylene glycol, polyalcohols with 3 to 6 carbon atoms, citric acid, citric acid esters, triethyl citrate, or combinations thereof.

4. The shell of claim 3, wherein the one or more plasticizers comprises from about 8% to about 30% by weight of the shell.

5. The shell of claim 1, further comprising a fill material.

6. The shell of claim 5, wherein the fill material comprises a liquid, semi-solid, or solid.

7. The shell of claim 5, wherein the fill material comprises one or more therapeutic, prophylactic, or diagnostic agents; and optionally one or more pharmaceutically acceptable excipients.

8. The shell of claim 1, wherein the pectin comprises high (methyl) ester pectin.

9. The shell of claim 1, wherein the pectin comprises low (methyl) ester pectin.

10. The shell of claim 1, wherein the pectin comprises amidated pectin.

11. The shell of claim 5, wherein the fill material comprises fish oil.

12. An oral gastric resistant dosage form comprising a soft capsule shell comprising (a) about 2% to about 5% pectin by weight of the capsule shell; (b) about 25% to about 40% gelatin by weight of the capsule shell; and (c) less than about 2% by weight of the capsule shell of a gelling agent comprising calcium salts, magnesium salts, or calcium gelatin; (d) about 8% to about 30% by weight of the capsule shell of a plasticizer comprising glycerol, sorbitol, or a combination thereof; and a fill comprising a pharmaceutically active agent or a nutritional, and optionally one or more pharmaceutically acceptable excipients.

13. An oral gastric resistant dosage form comprising a soft capsule shell encapsulating a fill, the shell comprising (a) about 2% to about 5% pectin by weight of the capsule shell; (b) about 25% to about 40% gelatin by weight of the capsule shell; and (c) less than about 2% by weight of the capsule shell of a gelling agent comprising calcium salts, and (d) about 8% to about 30% by weight of the capsule shell of a plasticizer comprising glycerol; and a fill comprising fish oil.

14. The shell of claim 3, wherein the plasticizer comprises glycerol.

15. The shell of claim 1, further comprising glycerol in an amount of about 8% to about 30% by weight of the capsule shell.

16. The shell of claim 1, further comprising water.

17. The shell of claim 1, wherein pectin comprises about 3% by weight of the capsule shell.

18. The shell of claim 1, wherein the gelling agent comprises a calcium salt.

19. The shell of claim 1, wherein the gelling agent comprises about 0.01% by weight of the capsule shell.

20. The dosage form of claim 12, wherein the plasticizer comprises glycerol.

21. The dosage form of claim 12, wherein the shell further comprises water.

22. The dosage form of claim 12, wherein pectin comprises about 3% by weight of the capsule shell.

23. The dosage form of claim 12, wherein the gelling agent comprises a calcium salt.

24. The dosage form of claim 12, wherein the gelling agent comprises about 0.01% by weight of the capsule shell.

25. The dosage form of claim 12, wherein the fill comprises fish oil.

26. The dosage form of claim 13, wherein the shell further comprises water.

27. The dosage form of claim 13, wherein pectin comprises about 3% by weight of the capsule shell.

28. The dosage form of claim 13, wherein the gelling agent comprises about 0.01% by weight of the capsule shell.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) I. Definitions

(2) Gastric resistant natural polymer as used herein refers to refers to natural polymers or mixtures of natural polymers which are insoluble in the acidic pH of the stomach.

(3) Film-forming natural polymer as used here refers to polymers useful for surface coatings that are applied by spraying, brushing, or various industrial processes, which undergo film formation. In most film-formation processes, a liquid coating of relatively low viscosity is applied to a solid substrate and is cured to a solid, high-molecular-weight, polymer-based adherent film possessing the properties desired by the user. For most common applications, this film has a thickness ranging from 0.5 to 500 micrometers (0.0005 to 0.5 millimeters, or 0.00002 to 0.02 inches).

(4) Gelling agent as used herein refers to substances that undergo a high degree of cross-linking or association when hydrated and dispersed in the dispersing medium, or when dissolved in the dispersing medium. This cross-linking or association of the dispersed phase alters the viscosity of the dispersing medium. The movement of the dispersing medium is restricted by the dispersed phase, and the viscosity is increased.

(5) II. Composition

(6) Gastric resistant film-forming compositions comprising (1) a gastric resistant natural polymer; (2) a film-forming natural polymer; and optionally (3) a gelling agent, are described herein.

(7) A. Gastric Resistant Natural Polymers

(8) Exemplary gastric resistant natural polymers include pectin and pectin-like polymers which typically consist mainly of galacturonic acid and galacturonic acid methyl ester units forming linear polysaccharide chains. Typically these polysaccharides are rich in galacturonic acid, rhamnose, arabinose and galactose, for example the polygalacturonans, rhamnogalacturonans and some arabinans, galactans and arabinogalactans. These are normally classified according to the degree of esterification. In high (methyl) ester (HM) pectin, a relatively high portion of the carboxyl groups occur as methyl esters, and the remaining carboxylic acid groups in the form of the free acid or as its ammonium, potassium, calcium or sodium salts; useful properties may vary with the degree of esterification and with the degree of polymerization. Pectin in which less than 50% of the carboxyl acid units occur as the methyl ester is normally referred to as low (methyl) ester or LM-pectin. In general, low ester pectin is obtained from high ester pectin by a treatment at mild acidic or alkaline conditions. Amidated pectin is obtained from high ester pectin when ammonia is used in the alkaline deesterification process. In this type of pectin some of the remaining carboxylic acid groups have been transformed into the acid amide. The useful properties of amidated pectin may vary with the proportion of ester and amide units and with the degree of polymerization.

(9) In one embodiment, the gastric resistant natural polymer is pectin. The gastric resistant natural polymer is present in an amount less than about 5% by weight of the composition, preferably from about 2 to about 4% by weight of the composition.

(10) B. Film-Forming Natural Polymers

(11) Exemplary film-forming natural polymers include gelatin and gelatin-like polymers. In a preferred embodiment, the film-forming natural polymer is gelatin. A number of other gelatin-like polymers are available commercially. The film-forming natural polymer is present in an amount from about 20 to about 40% by weigh of the composition, preferably from about 25 to about 40% by weight of the composition.

(12) C. Gelling Agent

(13) The composition can optionally contain a gelling agent. Exemplary gelling agents include divalent cations such as Ca.sup.2+ and Mg.sup.2+. Source of these ions include inorganic calcium and magnesium salts and calcium gelatin. The gelling agent is present in an amount less than about 2% by weight of the composition, preferably less than about 1% by weight of the composition.

(14) D. Plasticizers

(15) One or more plasticizers can be added to the composition to facilitate the film-forming process. Suitable plasticizers include glycerin, sorbitol, sorbitans, maltitol, glycerol, polyethylene glycol, polyalcohols with 3 to 6 carbon atoms, citric acid, citric acid esters, triethyl citrate and combinations thereof. The concentration of the one or more plasticizers is from about 8% to about 30% by weight of the composition. In one embodiment, the plasticizer is glycerin and/or sorbitol.

(16) III. Method of Making

(17) The film-forming composition can be used to prepare soft or hard shell gelatin capsules which can encapsulate a liquid or semi-solid fill material or a solid tablet (Softlet) comprising an active agent and one or more pharmaceutically acceptable excipients. Alternatively, the composition can be administered as a liquid with an active agent dissolved or dispersed in the composition.

(18) A. Capsules

(19) 1. Shell

(20) The film-forming composition can be used to prepare soft or hard capsules using techniques well known in the art. For example, soft capsules are typically produced using a rotary die encapsulation process. Fill formulations are fed into the encapsulation machine by gravity.

(21) The capsule shell can comprise one or more plasticizers selected from the group consisting of glycerin, sorbitol, sorbitans, maltitol, glycerol, polyethylene glycol, polyalcohols with 3 to 6 carbon atoms, citric acid, citric acid esters, triethyl citrate and combinations thereof.

(22) In addition to the plasticizer(s), the capsule shell can include other suitable shell additives such as opacifiers, colorants, humectants, preservatives, flavorings, and buffering salts and acids.

(23) Opacifiers are used to opacify the capsule shell when the encapsulated active agents are light sensitive. Suitable opacifiers include titanium dioxide, zinc oxide, calcium carbonate and combinations thereof.

(24) Colorants can be used to for marketing and product identification/differentiation purposes. Suitable colorants include synthetic and natural dyes and combinations thereof.

(25) Humectants can be used to suppress the water activity of the softgel. Suitable humectants include glycerin and sorbitol, which are often components of the plasticizer composition. Due to the low water activity of dried, properly stored softgels, the greatest risk from microorganisms comes from molds and yeasts. For this reason, preservatives can be incorporated into the capsule shell. Suitable preservatives include alkyl esters of p-hydroxy benzoic acid such as methyl, ethyl, propyl, butyl and heptyl (collectively known as parabens) or combinations thereof.

(26) Flavorings can be used to mask unpleasant odors and tastes of fill formulations. Suitable flavorings include synthetic and natural flavorings. The use of flavorings can be problematic due to the presence of aldehydes which can cross-link gelatin. As a result, buffering salts and acids can be used in conjunction with flavorings that contain aldehydes in order to inhibit cross-linking of the gelatin.

(27) 2. Fill Material Agents

(28) Soft capsules can used to deliver a wide variety of pharmaceutically active agents. Suitable agents include analgesics, anti-inflammatory agents, antihelmintics, anti-arrhythmic agents, anti-bacterial agents, anti-viral agents, anti-hypertensive agents, anti-coagulants, anti-depressants, anti-diabetics, anti-epileptics, anti-fungal agents, anti-gout agents, anti-malarials, anti-migraine agents, anti muscarinic agents, anti-neoplastic agents, erectile dysfunction improvement agents, immunosupressants, anti-protozoal agents, anti-thyroid agents, anxiolytic agents, sedatives, hypnotics, neuroleptics, -blockers, cardiac inotropic agents, corticosteroids, diuretics, anti-parkinsonian agents, gastro-intestinal agents, histamine H.sub.1 and H.sub.2 receptor antagonists, keratolytics, lipid regulating agents; anti-anginal agents, nutritional agents, opioid analgesics, sex hormones, stimulants, muscle relaxants, anti-osteoporosis agents, anti-obesity agents, cognition enhancers, anti-urinary incontinence agents, nutritional oils, anti-benign prostate hypertrophy agents, essential fatty acids, non essential fatty acids, vitamins, minerals and mixtures thereof.

(29) Excipients

(30) Fill formulations may be prepared using a pharmaceutically acceptable carrier composed of materials that are considered safe and effective and may be administered to an individual without causing undesirable biological side effects or unwanted interactions. The carrier is all components present in the pharmaceutical formulation other than the active ingredient or ingredients. As generally used herein carrier includes, but is not limited to surfactants, humectants, plasticizers, crystallization inhibitors, wetting agents, bulk filling agents, solubilizers, bioavailability enhancers, pH adjusting agents, and combinations thereof.

(31) B. Solutions and Suspensions

(32) Alternatively, the composition can be administered as a liquid with an active agent dissolved (e.g. solution) or dispersed (e.g. suspension) in the composition. Suitable active agents are described above. The solution or suspension may be prepared using one or more pharmaceutically acceptable excipients. Suitable excipients include, but are not limited to, surfactants, humectants, plasticizers, crystallization inhibitors, wetting agents, bulk filling agents, solubilizers, bioavailability enhancers, pH adjusting agents, flavorants and combinations thereof.

EXAMPLES

Example 1

Gastric Resistant Dosage Form

(33) The composition of the gastric resistant dosage form is shown below.

(34) TABLE-US-00001 Component % by weight of the Composition Pectin 4.04 Water 70.78 Calcium chloride (CaCl.sub.2) 0.05 Gelatin (150 bloom bovine bone) 17.70 Glycerin 7.43

Example 2

Gastric Resistant Dosage Form

(35) The composition of the gastric resistant dosage form is shown below.

(36) TABLE-US-00002 Component % by weight of the composition Pectin 4.04 Water 70.78 Calcium chloride (CaCl.sub.2) 0.05 Gelatin (175 bloom pig skin) 17.70 Glycerin 7.43

Example 3

Gastric Resistant Dosage Form

(37) The composition of the gastric resistant dosage form is shown below.

(38) TABLE-US-00003 Component % by weight of the composition Pectin 4.04 Water 70.71 Calcium chloride (CaCl.sub.2) 0.05 Gelatin (150 bloom bovine bone) 17.73 Glycerin 7.43

Example 4

Gastric Resistant Dosage Form

(39) The composition of the gastric dosage form is shown below.

(40) TABLE-US-00004 Component % by weight of the composition Pectin 4.04 Water 70.71 Calcium chloride (CaCl.sub.2) 0.03 Gelatin (150 bloom bovine bone) 17.75 Glycerin 7.43

Example 5

Gastric Resistant Dosage Form

(41) The composition of the gastric dosage form is shown below.

(42) TABLE-US-00005 Component % by weight of the composition Pectin 4.04 Water 70.71 Calcium chloride (CaCl.sub.2) 0.01 Gelatin (150 bloom bovine bone) 17.77 Glycerin 7.43

Example 6

Gastric Resistant Dosage Form

(43) The composition of the gastric dosage form is shown below.

(44) TABLE-US-00006 Component % by weight of the composition Pectin 4.04 Water 70.71 Calcium chloride (CaCl.sub.2) 0.007 Gelatin (150 bloom bovine bone) 17.77 Glycerin 7.43

Example 7

Gastric Resistant Dosage Form

(45) The composition of the gastric dosage form is shown below.

(46) TABLE-US-00007 Component % by weight of the composition Pectin 4.04 Water 68.99 Calcium chloride (CaCl.sub.2) 0.013 Gelatin (150 bloom bovine bone) 17.79 Glycerin 9.17

Example 8

Gastric Resistant Dosage Form

(47) The composition of the gastric dosage form is shown below.

(48) TABLE-US-00008 Component % by weight of the composition Pectin 4.04 Water 61.89 Calcium chloride (CaCl.sub.2) 0.013 Gelatin (150 bloom bovine bone) 22.79 Glycerin 11.27

Example 9

Gastric Resistant Dosage Form

(49) The composition of the gastric dosage form is shown below.

(50) TABLE-US-00009 Component % by weight of the composition Pectin 4.04 Water 54.79 Calcium chloride (CaCl.sub.2) 0.013 Gelatin (150 bloom bovine bone) 27.79 Glycerin 13.37

Example 10

Gastric Resistant Dosage Form

(51) The composition of the gastric dosage form is shown below.

(52) TABLE-US-00010 Component % by weight of the composition Pectin 4.04 Water 47.69 Calcium chloride (CaCl.sub.2) 0.013 Gelatin (150 bloom bovine bone) 32.79 Glycerin 15.47

Example 11

Gastric Resistant Dosage Form

(53) The composition of the gastric dosage form is shown below.

(54) TABLE-US-00011 Component % by weight of the composition Pectin 2.42 Water 49.11 Calcium chloride (CaCl.sub.2) 0.004 Gelatin (150 bloom bovine bone) 33.41 Glycerin 15.05

Example 12

Gastric Resistant Dosage Form

(55) The composition of the gastric dosage form is shown below.

(56) TABLE-US-00012 Component % by weight of the composition Pectin 2.42 Water 49.02 Calcium chloride (CaCl.sub.2) 0.008 Gelatin (150 bloom bovine bone) 33.60 Glycerin 15.05

Example 13

Gastric Resistant Dosage Form

(57) The composition of the gastric dosage form is shown below.

(58) TABLE-US-00013 Component % by weight of the composition Pectin 2.42 Water 49.11 Calcium chloride (CaCl.sub.2) 0.016 Gelatin (150 bloom bovine bone) 33.41 Glycerin 15.05

Example 14

Gastric Resistant Dosage Form

(59) The composition of the gastric dosage form is shown below.

(60) TABLE-US-00014 Component % by weight of the composition Pectin 2.42 Water 49.11 Calcium chloride (CaCl.sub.2) 0.031 Gelatin (150 bloom bovine bone) 33.39 Glycerin 15.05

Example 15

Gastric Resistant Dosage Form

(61) The composition of the gastric dosage form is shown below.

(62) TABLE-US-00015 Component % by weight of the composition Pectin 2.50 Water 47.69 Calcium chloride (CaCl.sub.2) 0.0054 Gelatin (150 bloom bovine bone) 34.33 Glycerin 15.47

Example 16

Gastric Resistant Dosage Form

(63) The composition of the gastric dosage form is shown below.

(64) TABLE-US-00016 Component % by weight of the composition Pectin 3.03 Water 49.11 Calcium chloride (CaCl.sub.2) 0.0049 Gelatin (150 bloom bovine bone) 32.81 Glycerin 15.05

Example 17

Gastric Resistant Dosage Form

(65) The composition of the gastric dosage form is shown below.

(66) TABLE-US-00017 Component % by weight of the composition Pectin 3.03 Water 47.68 Calcium chloride (CaCl.sub.2) 0.0065 Gelatin (150 bloom bovine bone) 33.81 Glycerin 15.47

Example 18

Gastric Resistant Dosage Form

(67) The composition of the gastric dosage form is shown below.

(68) TABLE-US-00018 Component % by weight of the composition Pectin 3.03 Water 49.11 Gelatin (150 bloom bovine bone) 32.81 Glycerin 15.05

(69) Typical fill materials include, but are not limited to, fish oil, garlic oil, soybean oil, and medium chain triglycerides (MCT).

(70) Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of skill in the art to which the disclosed invention belongs. Publications cited herein and the material for which they are cited are specifically incorporated by reference.

(71) Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.