Gastric reflux resistant dosage forms

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GASTRIC REFLUX RESISTANT DOSAGE FORMS FIELD OF THE INVENTION

The invention is in the field of gastric resistant dosage forms.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S.S .N. 11/316,830 filed in the

U.S. Patent and Trademark Office on 22 December 2005.

BACKGROUND OF THE INVENTION

The use and manufacture of enteric dosage forms are well known in the art. Such dosage forms are described in Remington’s Pharmaceutical 10 Sciences, 18^th Ed., Mack Publishing Co., Easton, PA (1990). Enteric dosage forms are useful for protecting the contents of the dosage form from the gastric conditions of the stomach and/or to protect gastric tissue from an

I irritant material contained in thUdosage form. Enteric dosage forms can also be useful in preventing gastric reflux due to the presence of odor-causing 15 liquids, such as fish oil or garlic oil, in the dosage form.

Enteric-coated dosage forms are typically produced by a film coating process, where a thin film layer of an acid-insoluble (enteric) polymer is applied to the surface of a pre-manufactured dosage form, such as a tablet, and to a lesser extent hard and soft capsules. The enteric coating method 20 involves spraying an aqueous or organic solution or suspension of one or more enteric polymers onto tumbling or moving tablets or capsules, followed by drying at elevated temperatures. Enteric dosage forms made by this coating method can suffer from various process-related problems that affect the performance and/or appearance of the coating. For example, “orange 25 peel” surface formation, also known as surface roughness or mottling, may result. More seriously, coat integrity failure may occur, such as cracking or flaking off of the enteric polymer coating. All coating processes present inherent problems, including possible uneven distribution of the coating ingredients, which can occur under multivariate coating processes.

These problems are common to all enteric dosage forms. However, the problems faced during the coating of gelatin or polysaccharide capsules are even more critical due to the delicate and heat sensitive nature of the soft

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Attempts to overcome the limitations associated with coated dosage forms have been made. For example, WO 2004/03068 by Banner

Pharmacaps, Inc. (“the ‘068 application”) describes a gel mass that is useful in manufacturing enteric soft or hard shell capsules or enteric tablets without the need for a coating. The gel mass contains a film-forming, water-soluble polymer, an acid-insoluble polymer and optionally, one or more excipients such as plasticizers, colorants and flavorants. The ‘068 application, however, discloses the use of synthetic acid-insoluble polymers such as cellulosic polymers and acrylic acid-methacrylic acid copolymers (EUDRAGIT®) which are present in a concentration from 8 to 20% by weight of the wet gel mass.

U.S. Patent Application Publication No. 2003/0175335 by Scott et al. (“the ’335 application”) describes film forming compositions containing pectin, at least one film-forming polymer, and a setting system for preparing soft and hard shell capsules. The concentration of pectin is 5 to 60% by weight, preferably 10 to 40% by weight. The concentration of the filmforming polymer is 40 to 95% by weight, preferably 50 to 85% by weight.

The ‘335 application discloses a film containing 5 to 25%, preferably 10 to 20% by weight pectin which is suitable to prepare hard shell capsules with enteric properties.

There exists a need for a gastric resistant film-forming composition that contains a gastric resistant natural polymer at relatively low concentrations.

Therefore, it is an object of the invention to provide a gastric resistant film-forming composition containing a gastric resistant film-forming

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It is further an object of the invention to provide a gastric resistant capsule shell, which can encapsulate a liquid, semi-solid, or solid fill, which 5 contains a gastric resistant natural polymer at relatively low concentrations and methods of manufacturing thereof.

BRIEF SUMMARY OF THE INVENTION

Gastric resistant film-forming compositions containing a gastric resistant natural polymer, a film-forming natural polymer, and optionally a 10 gelling agent are described herein. The compositions can be used for drug delivery either as a liquid or as a gelled capsule. Suitable gastric resistant natural polymers include polysaccharides such as pectin and pectin-like polymers. The concentration of the gastric resistant natural polymer is less than about 5% by weight of the composition, preferably from about 2 to 15 about 4% by weight of the composition. Suitable film-forming natural polymers include gelatin and gelatin-like polymers. The concentration of the film-forming natural polymer is from about 20 to about 40% by weight of the composition, preferably from about 25 to about 40% by weight of the composition. Suitable gelling agents include divalent cations such as Ca²⁺20 and Mg²*. The concentration of the optional gelling agent is less than about

2% by weight of the composition, preferably less than about 1% by weight of the composition. The composition can further contain one or more plasticizers to facilitate the film-forming process.

The film-forming composition can be used to prepare soft or hard 25 shell gelatin capsules which can encapsulate a liquid or semi-solid fill material or a solid tablet (SOFTLET®) containing 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 30 also prevent gastric reflux associated with odor causing liquids, such as fish oil or garlic oil, encapsulated in a unit dosage form as well as esophageal irritation due to the reflux of irritant drugs delivered orally.

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DETAILED DESCRIPTION OF THE INVENTION

I. Definitions “Gastric resistant natural polymer”, as used herein, refers to natural polymers or mixtures of natural polymers which are insoluble in the acidic pH of the stomach.

“Film-forming natural polymer”, as used herein, 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 o’f relatively low viscosity is applied to a solid 10 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 io 0.02 inches).

“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.

Π. Composition

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

A. Gastric Resistant Natural Polymers

Exemplary gastric resistant natural polymers include, but are not limited to, 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.

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In high (methyl) ester (“HM”) pectin, a relatively high portion of the carboxyl groups occur as methyl esters, and the remaining carboxylic acid groups are in the form of the free acid or as its ammonium, potassium, calcium or sodium salt. Useful properties may vary with the degree of 5 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 lo w (methyl) ester or LM-pectin. In general, low ester pectin is obtained from high ester pectin by treatment at mild acidic or alkaline conditions. Amidated pectin is obtained from high ester pectin when 10 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.

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.

B. Film-Forming Natural Polymers

Exemplary film-forming natural polymers include, but are not limited to, gelatin and gelatin-like polymers. In a preferred embodiment, the filmforming 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 weight of the composition, preferably from about 25 to about 40% by weight of the composition.

C. Gelling Agent

The compositions can optionally contain a gelling agent. Exemplary gelling agents include divalent cations such as Ca²⁺ and Mg²⁺. Sources of these ions include inorganic calcium and magnesium salts and calcium 30 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.

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D. Plasticizers

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 5 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.

III. Method of Making

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®) containing 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 15 the composition.

A. Capsules

1. Shell

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

The capsule shell can contain 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 25 acid esters, triethyl citrate and combinations thereof.

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.

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.

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

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 p10 hydroxy benzoic acid such as methyl, ethyl, propyl, butyl and heptyl (collectively known as “parabens”) or combinations thereof.

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 15 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.

2. Fill Material

i. Agents

Soft or hard capsules can used to deliver a wide variety of pharmaceutically active agents. Suitable agents include analgesics, antiinflammatory agents, antihelmintics, anti-arrhythmic agents, anti-bacterial agents, anti-viral agents, anti-hypertensive agents, anti-coagulants, antidepressants, anti-diabetics, anti-epileptics, anti-fungal agents, anti-gout agents, anti-malarials, anti-migraine agents, anti —muscarinic agents, antineoplastic 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 Hj and H2 receptor antagonists, keratolytics, lipid regulating agents, anti-anginal agents, nutritional agents, opioid analgesics, sex hormones, stimulants, muscle relaxants, anti-osteoporosis agents, anti7

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Typical fill materials include, but are not limited to, fish oil, garlic .

oil, soybean oil, peppermint oil, eucalyptus oil, horse chestnut seed extract, valproic acid, proton pump inhibitors, probiotics, and medium chain triglycerides (“MCT”).

ii. Excipients

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.

B. Solutions and Suspensions

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.

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Examples

The following film-forming compositions were used to prepare stable soft gelatin capsules using techniques well known in the art.

Example 1. Gastric Resistant Dosage Form

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

<td> Component</td><td> % by weight of the Composition I</td>

<td> I Pectin</td><td>^4,04 1</td>

<td> 1 Water</td><td> 70.78</td>

<td> Calcium chloride (CaCh)</td><td> 0.05</td>

<td> Gelatin (150 bloom bovine bone)</td><td> 17.70</td>

<td> Glycerin</td><td>^7,43</td>

Example 2. Gastric Resistant Dosage Form

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

<td> I Component</td><td> % by weight of the composition</td>

<td> « Pectin</td><td> 4.04</td>

<td> | Water</td><td> 70.78</td>

<td> I Calcium chloride (CaCh)</td><td> 0.05</td>

<td> | Gelatin (175 bloom pig skin)</td><td> 17.70</td>

<td> | Glycerin</td><td> 7.43</td>

Example 3. Gastric Resistant Dosage Form

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

<td> Component .</td><td> % by weight of the composition j</td>

<td> 1 Pectin</td><td> 4.04</td>

<td> Water</td><td> 70.71</td>

<td> Calcium chloride (CaCh)</td><td> 0.05</td>

<td> Gelatin (150 bloom bovine bone)</td><td> 17.73</td>

<td> | Glycerin</td><td> 7.43</td>

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Example 4. Gastric Resistant Dosage Form

The composition of the gastric dosage form is shown below.

<td> Component</td><td> % by weight of the composition I</td>

<td> Pectin</td><td> 4.04</td>

<td> Water</td><td> 70.71</td>

<td> Calcium chloride (CaCl₂)</td><td> 0.03</td>

<td> Gelatin (150 bloom bovine bone)</td><td> 17.75</td>

<td> Glycerin</td><td> 7.43</td>

Example 5. Gastric Resistant Dosage Form

The composition of the gastric dosage form is shown below.

<td> I Composent</td><td> % by weight of the composition I</td>

<td> 1 Pectin</td><td> 4.04</td>

<td> Water</td><td> 70.71</td>

<td> Calcium chloride (CaCl₂)</td><td> 0.01</td>

<td> | Gelatin (150 bloom bovine bone)</td><td> 17.77</td>

<td> | Glycerin</td><td> 7.43</td>

I

Example 6. Gastric Resistant Dosage Form

The composition of the gastric dosage form is shown below.

<td> 1 Component</td><td> % by weight of the composition I</td>

<td> Pectin</td><td> 4.04 1</td>

<td> Water</td><td> 70.71</td>

<td> Calcium chloride (CaCl₂)</td><td> 0.007</td>

<td> Gelatin (150 bloom bovine bone)</td><td> 17.77</td>

<td> Glycerin</td><td> 7.43</td>

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Example 7. Gastric Resistant Dosage Form

The composition of the gastric dosage form is shown below.

<td> Component</td><td> % by weight of the composition I</td>

<td> Pectin</td><td> 4.04</td>

<td> Water</td><td> 68.99</td>

<td> Calcium chloride (CaCh)</td><td> 0.013</td>

<td> I Gelatin (150 bloom bovine bone)</td><td> 17.79</td>

<td> Glycerin</td><td> 9.17</td>

Example 8. Gastric Resistant Dosage Form

The composition of the gastric dosage form is shown below.

<td> Component</td><td> % by weight of the composition</td>

<td> Pectin</td><td> 4.04</td>

<td> Water</td><td> 61.89</td>

<td> Calcium chloride (CaCl₂)</td><td> 0.013</td>

<td> Gelatin (150 bloom bovine bone)</td><td> 22.79</td>

<td> Glycerin</td><td>^11-27</td>

Example 9. Gastric Resistant Dosage Form

The composition of the gastric dosage form is shown below.

<td> Component</td><td> % by weight of the composition</td>

<td> Pectin</td><td> 4.04</td>

<td> Water</td><td> 54.79</td>

<td> Calcium chloride (CaCl₂)</td><td> 0.013</td>

<td> Gelatin (150 bloom bovine bone)</td><td> 27.79</td>

<td> Glycerin</td><td> 13.37</td>

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Example 10. Gastric Resistant Dosage Form

The composition of the gastric dosage form is shown below.

<td> Component</td><td> % by weight of the composition</td>

<td> Pectin</td><td> 4.04</td>

<td> Water</td><td> 47.69</td>

<td> Calcium chloride (CaCh)</td><td> 0.013</td>

<td> Gelatin (150 bloom bovine bone)</td><td> 32.79</td>

<td> | Glycerin</td><td> 15.47</td>

Example 11. Gastric Resistant Dosage Form

The composition of the gastric dosage form is shown below.

<td> I Component</td><td> % by weight of the composition</td>

<td> Pectin</td><td> 2.42</td>

<td> Water</td><td> 49.11</td>

<td> Calcium chloride (CaCl₂)</td><td> 0.004</td>

<td> Gelatin (150 bloom bovine bone)</td><td> 33.41</td>

<td> Glycerin</td><td> 15.05</td>

Example 12. Gastric Resistant Dosage Form

The composition of the gastric dosage form is shown below.

<td> ! Component</td><td> % by weight of the composition 8</td>

<td> Pectin</td><td> 2.42</td>

<td> Water</td><td> 49.02</td>

<td> | Calcium chloride (CaCl₂)</td><td> 0.008</td>

<td> Gelatin (150 bloom bovine bone)</td><td> 33.60</td>

<td> Glycerin</td><td> 15.05 1</td>

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Example 13. Gastric Resistant Dosage Form

The composition of the gastric dosage form is shown below.

<td> | Component</td><td> % by weight of the composition</td>

<td> Pectin</td><td> 2.42</td>

<td> Water</td><td> 49.11</td>

<td> Calcium chloride (CaCh)</td><td> 0.016</td>

<td> Gelatin (150 bloom bovine bone)</td><td> 33.41</td>

<td> Glycerin I</td><td> 15.05 1</td>

Example 14. Gastric Resistant Dosage Form

The composition of the gastric dosage form is shown below.

<td> I Component</td><td> % by weight of the composition</td>

<td> Pectin</td><td> 2.42</td>

<td> Water</td><td> 49.11</td>

<td> I Calcium chloride (CaCh)</td><td> 0.031</td>

<td> Gelatin (150 bloom bovine bone)</td><td> 33.39</td>

<td> Glycerin</td><td> 15.05 1</td>

Example 15. Gastric Resistant Dosage Form

The composition of the gastric dosage form is shown below.

<td> Component</td><td> % by weight of the composition |</td>

<td> Pectin</td><td> 2.50</td>

<td> Water</td><td> 47.69</td>

<td> Calcium chloride (CaCh)</td><td> 0.0054</td>

<td> | Gelatin (150 bloom bovine bone)</td><td> 34.33</td>

<td> | Glycerin</td><td> 15.47</td>

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Example 16. Gastric Resistant Dosage Form

The composition of the gastric dosage form is shown below.

<td> Component</td><td> % by weight of the composition 1</td>

<td> Pectin</td><td> 3.03</td>

<td> Water</td><td> 49.11</td>

<td> | Calcium chloride (CaCh)</td><td> 0.0049</td>

<td> 1 Gelatin (150 bloom bovine bone)</td><td> 32.81</td>

<td> I Glycerin</td><td> 15.05</td>

Example 17. Gastric Resistant Dosage Form

The composition of the gastric dosage form is shown, below.

<td> Component</td><td> % by weight of the composition 1</td>

<td> ' Pectin</td><td> 3.03</td>

<td> Water</td><td> 47.68</td>

<td> Calcium chloride (CaCh)</td><td> 0.0065</td>

<td> I Gelatin ( 15 0 bloom bovine bone)</td><td> 33.81</td>

<td> I Glycerin</td><td> 15.47</td>

Example 18. Gastric Resistant Dosage Form

The composition of the gastric dosage form is shown below.

<td> Component</td><td> % by weight of the composition I</td>

<td> Pectin .</td><td> 3.03</td>

<td> I Water</td><td> 49.11</td>

<td> Gelatin (150 bloom bovine bone)</td><td> 32.81</td>

<td> Glycerin</td><td> 15.05</td>

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.