WO2007098612A1

WO2007098612A1 - Gastric acid resistant gelatin capsule composition and method for producing same

Info

Publication number: WO2007098612A1
Application number: PCT/CA2007/000358
Authority: WO
Inventors: Tien Canh Le; Catherine Dupuis; Claudia Schlegel
Original assignee: Laboratoires Mauves Inc.
Priority date: 2006-03-02
Filing date: 2007-03-02
Publication date: 2007-09-07

Abstract

The present invention is to provide a process for preparing gastric acid resistant gelatin capsules. The process consists to add functional groups (i.e. carboxyl and/or acyl) in the gelatin backbone in order to confer to the gelatin a buffer capacity and a resistance in the gastric acid. Furthermore, the addition of polysaccharide (i.e. alginate) and fatty acid in the formulation is necessary to delay the disintegration of gelatin shell protecting thus the bioactive agents during gastric transit and deliver the bioactive agents at the absorption site in intestine.

Description

GASTRIC ACID RESISTANT GELATIN CAPSULE COMPOSITION AND METHOD FOR PRODUCING SAME

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority on US provisional application serial

60/778 ,104 filed March 2, 2006.

TECHNICAL FIELD

[0002] The present invention relates to gastric fluid resistant gelatin capsules for delivering past the stomach active ingredients or pharmaceutical products.

Background of the invention

[0003] Gelatin has the advantages of great availability, low cost, no toxicity, and being easily modifiable. However, sensitivity to moisture of gelatin constitutes an important problem to dosage forms with hydrosoluble drugs. Generally, there are two forms of gelatin based capsules, soft and hard gelatin capsules.

[0004] Soft gelatin capsule is generally used for encapsulating hydrophobic active molecules such as oils (i.e. primose oil) or liposoluble vitamins (i.e. vitamin E), while hard gelatin capsule has been used for drugs and herbal products, which are formulated either as a powder or pellets.

[0005] The presence of other substances such as glycerol as plasticizer can also constitute a problem. The moisture uptake of soft gelatin capsules plasticized with glycerol is considerably higher than that for hard gelatin capsules. Another effect of the plasticizer has been reported by Armstrong et al. (1984. J. Pharm. Pharmacol, 36, 361-365) who has shown that migration of a drug into the shell of a soft gelatin capsule can occur, which may result in drug degradation, less bioavailability of the drug and difficulties in assay. [0006] It is for the above reason that the applications for gelatin capsules generally are used mostly, if not limited to poorly water soluble drugs. The challenge is to find innovative ways of developing bioavailable and stable dosage forms. Excipient suppliers, encouraged by the potential opportunities in this field, are developing new materials comprising mixtures of functional excipients. An example is the introduction of Self Emulsifying Drug Delivery System (SMEDDS) by Gattefosse. Undoubtedly this approach was stimulated by the work performed by Sandoz, on the microemulsion formulation of cyclosporin A (Kovarik et al., 1994. J. Pharm. Sci., 83, 444-446).

[0007] Sensitivity to moisture is an aspect of a formulation which can be minimized by incorporating the drug into either a hydrophilic or lipophilic matrix. For example, the antibiotic vancomycin hydrochloride is highly hygroscopic and to achieve acceptable stability it needed to be formulated as a lyophilized powder for reconstitution. Bowtle et al. (1988, Pharm. Technol. 12, 86-97) successfully developed a hard gelatin capsule filled with a PEG 6000 matrix of the drug. This capsule formulation produced faecal, plasma and urine levels of the antibiotic that were similar to those obtained with the solution (Lucas et al., 1987. J. Clinical Pharmacy and Therapeutics, 12, 27-31 ) and is marketed by EIi Lilly as Vancocin® HCL.

[0008] By choosing an appropriate excipient the release rate of an active ingredient can be modified. For example Gelucire, which is available as a semisolid and can be mixed to obtain different drug release rates (Howard and Gould, 1987. Drug Dev. Ind. Pharm. 13, 1031-1045). Seta et al. (Int. J. Pharm. 41 , 263-269) compared the bioavailability of an oily semi-solid matrix of Captopril in hard gelatin capsules with that of a tablet. This product is marketed by Sankyo in Japan as Captoril®, and provides the patient with a more convenient dosage regime.

[0009] The challenge is to find simple yet innovative ways of developing stable dosage forms during gastric transit and greater bioavailability at the absorption sites in intestine. BRIEF SUMMARY OF THE INVENTION

[0010] One aim of the present invention is to provide a dosage form that can sustain gastric transit and allow availability of the active ingredient delivered with this dosage form at the absorption site in the intestine.

[0011] The present invention discloses functionalized gelatin modified by adding carboxylate groups and/or acyl chains to be used as carriers of bioactive agents under various forms (capsules, spheres, films, hydrogel, etc.) hereinafter referred to as a dosage form. The addition of carboxylate groups confers to the gelatin a buffer capacity and the acyl chains constitute a barrier limiting the access of gastric fluid, thus protecting the sensitive bioactive agents during gastric transit (pH 1.2-2.0). Furthermore, the addition of polysaccharide (i.e. alginate) in the formulation using as matrix is necessary to delay the disintegration of gelatin shell protecting thus the bioactive agents during gastric transit.

[0012] In accordance with the present invention there is provided a gastric- resistant gelatin composition for use in the preparation of dosage forms, said gelatin composition comprising:

30-60 % (w/w of the composition) of gelatin;

0.1-10 % (w/w of the composition) of a functionalizing agent containing a carboxylate group or an acyl chain containing group, said functionalizing agent comprising i) a carboxylate group or an acyl chain containing group, and a reactive group capable of reacting the gelatin for attaching covalently said carboxylate group or said acyl chain containing group to the gelatin; and

0.1-10 % (w/w of the composition) of a negatively charged polysaccharide.

[0013] In accordance with the present invention, there is still provided a method for manufacturing a gelatin composition for use in the preparation of dosage forms, said method comprising the steps of: - A - i) dispersing 30-60 % (w/w of the composition) of gelatin in a solution of 0.1-10 % (w/w of the composition) of a negatively charged polysaccharide to create an emulsion; and

ii) stirring into said emulsion 0.1-10 % (w/w of the composition) of a functionalizing agent containing a carboxylate group or an acyl chain containing group and a reactive group capable of reacting the gelatin for attaching covalently said carboxylate group or said acyl chain containing group to the gelatin, for a time sufficient for said functionalizing agent to attach covalently said carboxylate group or said acyl chain containing group to the gelatin to obtain an emulsion of functionalized gelatin in the solution of the negatively charged polysaccharide.

[0014] In one embodiment, the method may further comprise in step i) the addition of 0.5-15% (w/w of the composition) of a lipid before dispersing said gelatin in the solution.

[0015] In another embodiment, the method may further comprise in step i) the addition of 0.5-10% (w/w of the composition) of an emulsifier before dispersing said gelatin in the solution.

[0016] Further in accordance with the present invention, there is also provided a method for manufacturing a gelatin composition for use in the preparation of dosage forms, said method comprising the steps of:

i) Contacting 0.1-10 % (w/w of the composition) of a functionalizing agent containing a carboxylate group or an acyl chain containing group and a reactive group capable of reacting the gelatin for attaching covalently said carboxylate group or said acyl chain containing group to the gelatin, with a solution of 30-60 % (w/w of the composition) of gelatin for a time sufficient for said functionalizing agent to attach covalently said carboxylate group or said acyl chain containing group to the gelatin to obtain a solution of functionalized gelatin; and

ii) Adding to the solution of functionalized gelatin a solution of 0.1-10 % (w/w of the composition) of a negatively charged polysaccharide for completing said composition.

[0017] In one embodiment, the method may further comprise at step ii) the addition of 0.5-15% (w/w of the composition) of a lipid to the negatively charged polysaccharide.

[0018] In another embodiment, the method may further comprise at step ii) the further addition of 0.5-10% (w/w of the composition) of an emulsifier to the negatively charged polysaccharide.

[0019] For the purpose of the present invention the following terms are defined below.

[0020] The term "functionalized gelatin" is intended to refer to gelatin that has been modified with the addition of carboxylate groups and/or acyl chains.

[0021] The expression "buffer capacity" refers to the capacity of the gelatin to resist acid degradation or dissolution by trapping protons from the gastric environment on the carboxylate groups added to the gelatin.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING

[0022] Fig. 1 illustrates the functionalization of gelatin with a succinyl anhydride, also referred to as succinylation;

[0023] Fig. 2 illustrates the functionalization that could be carried out with alkenylsuccinic anhydride allowing the introduction of carboxylate groups including an acyl chain on the gelatin (R= alkenyl chain, C4-C18);

[0024] Fig. 3 illustrates the profile of disintegration of gelatin (1 ), succinylated gelatin (2), succinylated gelatin containing an alginic matrix (3) or succinylated gelatin containing an alginic matrix and stearic acid (4); and [0025] Fig. 4 illustrates the profile of disintegration of gelatin containing either no stearic acid (1 ), 1.0% (2), 1.5% (3) or 2% (4) stearic acid.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

[0026] The present invention relates to an improvement of gelatin drug device. The invention also provides a shell composition for use in constructing soft or hard gelatin capsules resistant in the gastric fluid. The composition of capsule consists mainly in functionalized gelatin, polysaccharide matrix and optionally lipids compound.

[0027] The present invention relates to a gastric fluid resistant gelatin dosage form. More particularly, the invention relates to pharmaceutical dosage forms having a shell which is able to travel through the stomach and its acid environment such that drugs which are acid sensitive can be delivered to the intestine without being affected by the acid environment of the stomach. More particularly, the gelatin dosage form has proton traps (or "proton scavenger") to neutralize the gastric acid, thus protecting the drugs during gastric transit and delivering the bioactive agents at the action sites in intestine.

[0028] Thus, in one embodiment, the present invention consists in adding carboxylate groups on gelatin in order to confer to the dosage form a "buffer capacity" to trap protons and thus neutralize the gastric acid migrating through the gelatin. It is noteworthy that the buffer capacity can be improved by the addition of polysaccharides (such as alginate which possesses carboxylate groups). Moreover, these polysaccharides can also serve as a matrix to stabilize the gelatin in acidic medium and postpone the disintegration of gelatin, thus delaying the release of any bioactive agents contained in the gelatin dosage form until they are no longer in the stomach.

[0029] Although the functionalization can confer to the gelatin dosage form a buffer property, its buffering capacity is however limited. Therefore, in one embodiment of the invention, to improve the "buffer capacity" of the gelatin dosage form, lipid compounds can be added to the gelatin dosage form to increase the gelatin hydrophobicity which limits the migration of gastric acid through the gelatin dosage form. In this case, the use of an emulsifying agent is preferred in order to more uniformly disperse the lipid compound in the gelatin.

[0030] In one embodiment of the invention, the process for preparing functionalized gelatin dosage forms such as capsules that would be resistant to the gastric acid comprise the steps of:

i) preparing a mixing solution of polysaccharide (i.e. alginate) and emulsifying agent (i.e. lecithin); ii) adding a lipid compound at the suitable temperature (such that the lipid compound is liquid) to obtain a uniform emulsion suspension; iii) dispersing the gelatin in the mixture obtained in ii); iv) functionalizing the gelatin by introducing a functionalizing agent (such as succinic anhydride) in the emulsion of step iii).

[0031] It is of interest to note that the gelatin could be functionalized just prior to add in the mixture solution and in this case, the step (iv) is not necessary.

[0032] The emulsion so obtained in step iv) can thereafter be used to produce gelatin dosage forms such as capsules, spheres, films, hydrogels, etc. In the above method, one skilled in the art will appreciate that functionalizing the gelatin is also possible to be made directly on a solution of gelatin, prior to said solution being added to the emulsion of step ii). In such case, the addition of the gelatin at step iii) and the step of functionalizing at step iv) are both replaced with a step iiia) which comprises the addition to the emulsion of step ii) a solution of functionalized gelatin.

[0033] In the present invention, the gelatin capsule define in this invention may take any form of various capsules such as a hard or soft capsule. Furthermore, the form and the size of the capsule are not limited. For example, the gelatin capsule can be spherical, oval, oblong, and tubular or tear-drop form, while the capsule size can vary from several micrometers to several centimeters. [0034] For producing a soft capsule, a rotary die process could be used in which capsule formation, filling of contents and heat sealing are conducted simultaneously using two sheets.

[0035] For producing a hard capsule, a dipping method is used in which the capsule is formed by introducing a mould pin in a film-forming solution followed by drying.

Polysaccharide matrices

[0036] In a preferred embodiment of the present invention, the polysaccharides that can make such matrix within the gelatin are selected from negatively charged polysaccharides or polysaccharides possessing a functional (e.g. carboxylate, sulfate or phosphate, etc). Various polysaccharides can be added in the formulations to improve the buffer capacity or the resistance to the gastric fluid, such as alginate, hyaluronate, pectin, carrageenan, chitosan, xanthan, galactomanan, etc. or any combination thereof. These charged polysaccharides stabilize the gelatin by hydrogen and ionic interactions. Some of these charged polysaccharides gel or coagulate in an acid media, such that resistance to gastric fluid is improved, thus consolidating the capsular gelatin membrane. In one embodiment, preferably alginic acid sodium salt (alginate) is used. This polysaccharide often used in the pharmaceutical preparations as anti-acid due to the presence of carboxylate groups which can scavenge protons of gastric acid. Furthermore, alginate gels and remains insoluble in the gastric medium preventing the disintegration of capsular gelatin and release of bioactive agents in the stomach. On the other hand, alginate becomes soluble in the intestinal medium permitting thus the gelatin dissolution and release of bioactive agent at the action sites. Generally, the matrix-forming polysaccharide is used at a rate of about 0.1-10% of mixing solution. Emulsifying agent

[0037] The emulsifying agent used some embodiments of this invention to uniformly disperse the lipid components added in the formulation in order to improve the hydrophobicity of the gelatin membrane. Useful emulsifying agents include ionic (anionic or cationic) or amphoteric compounds (zwitterions containing both positive and negative charges) and preferably phosphatidylcholin (lecithin), phosphatidylserine, phosphatidyl ethanolamine, phsphatidylinositol, etc. or any mixture thereof. It is worth to mention that these compounds can ionically interact with the polysaccharide matrix and contribute not only to disperse the lipid compounds but also to stabilize the matrix. Their quantity could be varied from about 0.5% up to 10% according to the amount of lipid introduced in the formulation.

Lipid compound

[0038] To improve the resistance of gastric fluid, numerous lipid compounds could be added in the formulation such as fatty acids (stearic acid, oleic acid, palmitic acid, etc.) mineral oils, vegetal oils (canola oil, flax oil, soybean oil, etc.), polycaprolactone, etc. These lipid compounds increase the hydrophobicity of gelatin capsule playing a role of barrier which limits the water or gastric fluid migration through the gelatin capsule. The lipid compounds may be present in an amount from about 0.5-15% of mixing solution.

Gelatin

[0039] In the present invention, the gelatin could be selected from bovine gelatin, pig gelatin, fish gelatin or from any other sources (skin or bone). The contents of gelatin in mixing solution comprise from about 30-60%.

Functionalizinq agent

[0040] The addition of carboxylate groups on the gelatin could be achieved using functionalizing agents such as succinic anhydride (Fig. 1 ), glutaric anhydride, maleic anhydride, isovaleric anhydride, diglycolic anhydride, monochloracetic acid, etc. For acylation of gelatin, several functionalizing agents could be used such as acyl chloride (palmitoyl chloride, steroyl chloride, myristoyl chloride, etc.), anhydride of fatty acids (myristic anhydride, palmitic anhydride, erucic anhydride, heptanoic anhydride, etc.).

[0041] Another aspect in this embodiment is that the addition of carboxylate groups or acyl chains on the gelatin could be achieved in one step using the functionalizing agents such as: dodecenylsuccinic anhydride, nonenylsuccinic anhydride, 2-dodecen-1-yl-succinic anhydride, etc. (Fig. 2). [0042] The lists of functionalizing agents noted herein is not meant be exhaustive, but simply indicative of the groups of agents that one skilled in the art may choose from. Furthermore, the gelatin functionalization could be carried out just prior to make the capsule or pre-functionalized for «ready-to-use». In the last case, the functionalizing agent (preferably succinic anhydride) is added during the process of extraction and transformation of gelatin. In general, the amount of functionalizing agent added in the mixing solution is varied from about 0.1-10%.

[0043] It is of interest to note that the reaction with succinic anhydride is rapid and can be made at a low cost without using a solvent. Moreover, the secondary product obtained in a gastric acid attack is succinic acid (resulting of succinic acid and water) which occurs naturally in the Krebs cycle. It is also used in pharmaceuticals and perfumes. The succinylated gelatin is known to be non-toxic and is considered GRAS (Generally Recognized As Safe) for use in gelatin. Tosaki et al. (Nippon Rinsho, 26, 5, 1227-1233, 1968) reported that succinylated gelatin can use as a plasma substitute. The latter was known under commercial name «Gelofusine».

Other ingredients

[0044] The gelatin dosage forms of the present invention can include other additives. For example, plasticizer such as glycerol, propylen glycol, sorbitol, etc. is optionally added to improve the rheological (viscoelasticity) properties of capsules. An antibacterial agent such as propionic acid, sorbic acid, benzoic acid, etc. could also be used to prevent bacteria contaminations. The addition of flavoring agent, coloring agent or sweetener is also possible to mask the odor or taste of the bioactive agent or impart specific characteristics and in in certain cases, an antioxidant such as butylated hydroxyanisole (BHA) or butylated hydroxytoluene (BHT) can be added to protect bioactive agents sensitive to the oxidation. It is important to note that the total amount of these other ingredients are generally used in the formulation in relatively small quantities varying from about 0 to about 15%. [0045] Additionally, the formulation in this invention could be used as supports to immobilize the bioactive agents which are to be incorporated by entrapment. These bioactive agents include bioactive peptides (bacteriocin, insulin, vaccine) or proteins (enzyme), bacteria cells and various drugs, etc. The main support role consists of protecting these bioactive agents during gastric transit and delivering them to action sites in the intestine.

[0046] Below are examples illustrating several soft gelatin shell compositions made in accordance with the present invention. The examples presented below illustrate particular embodiment of the invention and is not intended to limit the scope of the specification.

[0047] The present invention will be more readily understood by referring to the following examples which are given to illustrate the invention rather than to limit its scope.

EXAMPLE I Preparation of functionalized gelatin with alginic matrix

Succinylation of gelatin

[0048] An amount of 35 g of gelatin was dispersed in 50 g of water containing 1.5 g of alginic acid sodium salt (alginate) and heated at 60 ⁰C under stirring. The pH was adjusted to 6.0-6.5 with diluted NaOH (0.1 M) and 1.5 g of solid succinic anhydride was slowly added over 15 minutes. It is possibly to dissolve the succinic anhydride in the methanol or ethanol just prior to add in the gelatin solution. The mixture was stirred for at least 2 hours and the suspension was completed to 100 g.

EXAMPLE Il

Preparation of functionalized gelatin with alginate matrix in presence of stearic acid

Step 1 - Preparation of alginate/lecithin mixing solution [0049] An amount of 1.5 g of alginate was slowly added in the solution containing 2.0 g of glycerol and 58 g of purified water and the solution is stirred at 60 ⁰C. After complete dispersion of alginate, an amount of 1.5 g of lecithin was introduced in the solution and stirred until obtaining a homogenized suspension.

Step 2 - Preparation of lipid / matrix emulsion solution [0050] An amount of 1 g of stearic acid was beforehand melted at 75 ⁰C and added in the alginate / lecithin mixing solution at the same temperature under moderated stirring during at least 10 minutes for the formation of emulsion.

Step 3 - Dispersion of gelatin in the lipid / matrix emulsion solution [0051] Just prior to the gelatin addition, the temperature of the mixture prepared above (step 2) was reported at 65-70 ⁰C. Then, a quantity of 35 g of gelatin (Weishardt International, Graulhet Cedex, France) was slowly added in the mixture. The solution was increasingly viscous which requires a strong stirring, (je

Step 4 - Succinylation of gelatin

[0052] After dispersion complete of gelatin, an amount of 1.0 g of succinic anhydride was slowly added in the gelatin suspension. Also, it is possible to dissolve the succinic anhydride in a minimum quantity of methanol or ethanol (5-10 ml_) just prior to add in the mixture solution. The succinylation reaction was operated under stirring at 70 ⁰C during at least 1 hour.

[0053] In some cases It may be preferred to functionalize the gelatin such as with succinyl anhydride, in which case the functionalized gelatine is thereafter added in the mixture. For this purpose, the functionalization process can be carried out for example by dispersing 35 % of gelatin in 60 ml_ of water at 70 ⁰C. The pH of the solution is adjusted about 6.0-6.5 with diluted NaOH solution under stirring. After gelatin complete solubilization, suitable functionalizing agent is slowly added during at least 1 hour. When the reaction completed, the functionalized gelatin suspension is then chilled and either cut in ribbons or extruded as noodles and then dried for at least 5 hours. Finally, the functionalized gelatin can be broken into pieces that are ground to the required particle size. Step 5 - Capsule formation

[0054] The solution obtained in step 4 was cooled at temperature of about 45 ⁰C at which capsules are made with suitable process to obtain the hard or soft gelatin capsule (as described previously).

EXEMPLE III

Gelatin capsule compositions.

[0055] Illustrated below are several gelatin capsule compositions according to the present invention. The compositions presented below illustrate particular embodiment of the invention and is not intended to limit the scope of the specification.

Composition 1

Fill Ingredients % by wt.

Gelatin 35-45

Sorbitol 5-15

Succinic anhydride 1-10

Purified water 10-30

Composition 2

Fill Ingredients % by wt.

Gelatin 20-45

Sorbitol 5-10

Succinic anhydride 1-10

Glycerol 1-5

Purified water 10-30 Composition 3

Fill Ingredients % by wt.

Gelatin 35-45

Sorbitol 5-10

Succinic anhydride 1-10

Palmitoyl chloride 1-5

Purified water 10-30

Composition 4

Fill Ingredients % by wt.

Gelatin 20-45

Sorbitol 5-10

Glutaric anhydride 1-10

Palmitoyl chloride 1-5

Glycerol 1-5

Purified Water 10-25

Composition 5

Fill Ingredients % by wt.

Gelatin 20-45

Sorbitol 5-10

Succinic anhydride 1-10

Mineral Oil, light or heavy 1-5

Purified water 10-30 Composition 6

Fill Ingredients % by wt.

Gelatin 30-45

Sorbitol 5-10

Glutaric anhydride 1-10

Canola Oil 1-5

Purified water 10-30

Composition 7

Fill Ingredients % by wt.

Gelatin 30-40

Sorbitol 5-10

Succinic anhydride 1-10

Alginic acid, sodium salt 1-5

Mineral Oil, light or heavy 1-5

Purified water 10-30

Composition 8

Fill Ingredients % by wt.

Gelatin 30-40

Sorbitol 5-10

2-Dodecen-1 -ylsuccinic anhydride 1-10

Xanthan Gum 1-5

Glycerol 1-5

Soya Bean Oil 1-5

Purified water 1-25 Composition 9

Fill Ingredients % by wt.

Gelatin 30-40

Sorbitol 5-10

Succinic anhydride 1-10

Alginic acid, sodium salt 1-5

Glycerol 1-5

Mineral Oil, light or heavy 1-5

Purified water 10-25

Composition 10

Fill Ingredients % by wt.

Gelatin 30-40

Sorbitol 5-10

Succinic anhydride 1-10

Alginic acid, sodium salt 1-5

Glycerol 1-5

Lin Oil 1-5

Purified water 10-25

Composition 11

Fill Ingredients % by wt.

Gelatin 30-45

Sorbitol 5-10

Succinic anhydride 1-10

Hyaluronic acid, sodium salt 1-5

Purified water 10-30 Composition 12

Fill Ingredients % by wt.

Gelatin 30-40

Sorbitol 5-10

Maleic anhydride 1-10

Arabic Gum 1-5

Glycerol 1-5

Purified water 10-30

Composition 13

Fill Ingredients % by wt.

Gelatin 30-40

Sorbitol 5-10

Succinic anhydride 1-10

Karaya Gum 1-5

Glycerol 1-5

Mineral Oil, light or heavy 1-5

Purified water 10-25

Composition 14

Fill Ingredients % by wt.

Gelatin 20-40

Sorbitol 5-10

Succinic anhydride 1-10

Sodium carboxymethylcellulose 1-5

Glycerol 1-5

Peanut Oil 1-5

Purified water 10-25 Composition 15

Fill Ingredients % by wt.

Gelatin 20-45

Sorbitol 5-15

Myristoyl Chloride 1-10

Purified water 10-30

Composition 16

Fill Ingredients % by wt.

Gelatin 20-45

Sorbitol 5-15

Hexanoyl Chloride 1-10

Glycerol 1-5

Purified water 10-25

Composition 17

Fill Ingredients % by wt.

Gelatin 20-45

Sorbitol 5-15

4-Pentenoyl Chloride 1-5

Alginic acid, sodium salt 1-5

Purified water 10-30 Composition 18

Fill Ingredients % by wt.

Gelatin 20-45

Sorbitol 5-10

Heptanoyl Chloride 1-10

Alginic acid, sodium salt 1-5

Glycerol 1-5

Purified water 10-25

EXAMPLE IV

Acid resistance of succinylated and nonenylsuccinylated gelatin

[0056] The nonenylsuccinyl gelatin is made as described in Example I above with the exception that nonenylsuccinyl anhydride is substituted to succinyl anhydride. In this test, succinylated gelatine and nonenylsuccinylated gelatine were compared to untreated (non-functionalized) gelatine.

[0057] To test the buffer capacity of a nonenylsuccinylated gelatin, a gelatin film was preferably formed by casting 4-5 g of nonenylsuccinylated gelatin solution or film-forming solution (obtained above in Example I) onto the Petri dishes (8.5 cm diameter) and allowed to dry overnight (to form a film) and thereafter kept at 22 ±1 °C with 50% relative humidity for three days. A similar film was prepared with succinylated gelatin and for non-functionalized gelatin. The buffer capacity of the three gelatin films was determined by individually immersing the dried films in 100 imL of simulated gastric fluid solution (pH 2, USP method 27) containing bromophenol blue. After 15 minutes at 37 ⁰C, the solution containing the functionalized gelatin (succinylated or nonenylsuccinylated) with or without alginate film changes the color from yellow (pH <3.0) to lavender (pH > 4.5), while the non-functionalized gelatin film remains unchanged, showing the buffer effect of the functionalized gelatin. EXAMPLE V Disintegration test

[0058] For instance, dried gelatin films (thickness 200-250 mm) were used for the disintegration test according to the USP dissolution using the paddle method. Dried films (obtained as described in Example 1 ) of 100 mg were placed in 1 L of simulated gastric fluid (pH 1.2, at 37 ⁰C), but without pepsin. The dissolution kinetics was monitored at 100 rpm within 1 hour by UV absorbance at 218 nm (Ultrospec Plus spectrophotometer, Pharmacia-LKB, England). Each data point is the average of four single tests.

[0059] The disintegration profile of gelatin is represented in Fig. 3. Indeed, the presence of alginate matrix permitted to prolong time of dissolution of the gelatin in comparison with non-treated gelatin. Furthermore, the addition of stearic acid increased the time of resistance to degradation even more. Generally, the best results were obtained with the addition of alginate and stearic acid.

[0060] It is of interest to mention that using high stearic acid quantities, gelatin could loose its sealability property. With regard to the gelatin, its disintegration was delayed for weak functionalization degrees. To the opposite, at high functionalized degrees, the gelatin become more soluble and dissolved rapidly in acid medium.

Example Vl

Preparation of functionalized gelatin with alginate matrix in the presence of various stearic acid quantities

[0061] The formulation was prepared as described previously in Example II. Various quantities of stearic acid (0-2 g) were introduced in different formulations. The disintegration profile is represented in Fig. 4. Example VII

Preparation of functionalized gelatin with alginate matrix in the presence of different lipid compounds

[0062] The formulation was prepared as described previously in example 2, but instead of using alginate, it was replaced alternatively by mineral oil, canola oil or polycaprolactone. The best results were obtained with the composition containing the mineral oil followed by the composition containing the polycaprolactone. Moreover, the formulation with mineral oil presented a similar gelatin disintegration profile in comparing with that containing stearic acid.

Example VIII

Preparation of gastric fluid resistant gelatin capsules with other polysaccharide matrix

[0063] Similarly, the formulations were prepared as described in Example II, but instead of using alginate, i carrageenan (preferably the kappa or iota form), pectin or xanthan gum were used.

[0064] The gelatin disintegration profile shows that no significant difference was noticed for the carrageenan and pectin matrices in comparing with that of alginate. However, the disintegration time with the xanthan matrix was slightly shorter.

[0065] While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth, and as follows in the scope of the appended claims.

Claims

WHAT IS CLAIMED IS:

1. A gastric-resistant gelatin composition for use in the preparation of dosage forms, said gelatin composition comprising:

30-60 % (w/w of the composition) of gelatin;

0.1-10 % (w/w of the composition) of a negatively charged polysaccharide.

2. The gelatin composition of claim 1 , further comprising 0.5-15% (w/w of the composition) of a lipid.

3. The gelatin composition of claim 1 , further comprising 0.5-10% (w/w of the composition) of an emulsifier.

4. The gelatin composition of any one of claims 1 to 3, wherein the polysaccharide is selected from the group consisting of alginate, hyaluronate, pectin, carrageenan, xanthan, and galactomanan or combination thereof.

5. The gelatin composition of any one of claims 1 to 3, wherein the polysaccharide is alginate.

6. The gelatin composition of any one of claims 1 to 3, wherein the lipid is selected from the group consisting of fatty acids, preferably stearic acid, oleic acid and palmitic acid, mineral oils, vegetal oils, preferably canola oil, Nn oil, soybean oil, and polycaprolactone.

7. The gelatin composition of any one of claims 1 to 3, wherein the emulsifying agent is selected from the group consisting of ionic and amphoteric compounds.

8. The gelatin composition of claim 7, wherein the emulsifying agent is selected from the group consisting of zwitterions, phosphatidylcholin, phosphatidylserine, phosphatidyl ethanolamine, and phsphatidylinositol, or a mixture thereof.

9. The gelatin composition of any one of claims 1 to 3, wherein the gelatin is porcine gelatin, bovine gelatin or fish gelatin, obtained from either skin, bones or cartilage.

10. The gelatin composition of any one of claims 1 to 3, wherein the functionalizing agent comprising a carboxylate group is selected from the group consisting of succinic anhydride, glutaric anhydride, maleic anhydride, isovaleric anhydride, diglycolic anhydride, and monochloracetic acid.

11. The gelatin composition of any one of claims 1 to 3, wherein the functionalizing agent comprising an acyl chain containing group is selected from the group consisting of acyl chloride, anhydride of fatty acids, dodecenylsuccinic anhydride, nonenylsuccinic anhydride, and 2- dodecen-1-yl-succinic anhydride.

12. The gelatin composition of claim 11 , wherein the acyl chloride is selected from the group consisting of palmitoyl chloride, steroyl chloride, and myristoyl chloride.

13. The gelatin composition of claim 11 , wherein the anhydride of fatty acids is selected from the group consisting of myristic anhydride, palmitic anhydride, erucic anhydride, and heptanoic anhydride.

14. The gelatin composition of any one of claims 1 to 3, wherein the functionalizing agent is succinic anhydride.

15. The gelatin composition of any one of claims 1 to 3, further comprising at least one other ingredients selected from the group consisting of a plastifier, an antibacterial agent, a flavoring agent, a coloring agent, a sweetener, and an antioxidant.

16. The gelatin composition of claim 15, wherein said plastifier is selected from the group consisting of glycerol, propylen glycol, and sorbitol.

17. The gelatin composition of claim 15, wherein said antibacterial agent is selected from the group consisting of propionic acid, sorbic acid, and benzoic acid.

18. The gelatin composition of claim 15, wherein said antioxidant is selected from the group consisting of butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT).

19. Use of the gelatin composition as defined in any one of claims 1 to 18, for the manufacture of a dosage form selected from the group consisting of capsules, spheres, films, and hydrogels.

20. Use of the gelatin composition as defined in any one of claims 1 to 18, for encapsulating or entrapping a bioactive agent.

21. The use of claim 20, wherein the bioactive agent in selected from the group consisting of a bioactive peptide, a protein, bacteria, and a pharmaceutical drug.

22. A method for manufacturing a gelatin composition for use in the preparation of dosage forms, said method comprising the steps of: i) dispersing 30-60 % (w/w of the composition) of gelatin in a solution of 0.1-10 % (w/w of the composition) of a negatively charged polysaccharide to create an emulsion; and

23. The method of claim 22, further comprising in step i) the addition of 0.5- 15% (w/w of the composition) of a lipid before dispersing said gelatin in the solution.

24. The method of claim 23, further comprising in step i) the addition of 0.5- 10% (w/w of the composition) of an emulsifier before dispersing said gelatin in the solution.

25. The method of any one of claims 22 to 24, wherein the polysaccharide is selected from the group consisting of alginate, hyaluronate, pectin, carrageenan, xanthan, and galactomanan or a combination thereof.

26. The method of any one of claims 22 to 24, wherein the polysaccharide is alginate.

27. The method of any one of claims 22 to 24, wherein the lipid is selected from the group consisting of fatty acids, preferably stearic acid, oleic acid and palmitic acid, mineral oils, vegetal oils, preferably canola oil, lin oil, soybean oil, and polycaprolactone.

28. The method of any one of claims 22 to 24, wherein the emulsifying agent is selected from the group consisting of ionic and amphoteric compounds.

29. The method of claim 28, wherein the emulsifying agent is selected from the group consisting of zwitterions, phosphatidylcholin, phosphatidylserine, phosphatidyl ethanolamine, and phsphatidylinositol, or a mixture thereof.

30. The method of any one of claims 22 to 24, wherein the gelatin is porcine gelatin, bovine gelatin or fish gelatin, obtained from either skin, bones or cartilage.

31. The method of any one of claims 22 to 24, wherein the functionalizing agent comprising a carboxylate group is selected from the group consisting of succinic anhydride, glutaric anhydride, maleic anhydride, isovaleric anhydride, diglycolic anhydride, and monochloracetic acid.

32. The method of any one of claims 22 to 24, wherein the functionalizing agent comprising an acyl chain containing group is selected from the group consisting of acyl chloride, anhydride of fatty acids, dodecenylsuccinic anhydride, nonenylsuccinic anhydride, and 2- dodecen-1-yl-succinic anhydride.

33. The method of claim 32, wherein the acyl chloride is selected from the group consisting of palmitoyl chloride, steroyl chloride, and myristoyl chloride.

34. The method of claim 32, wherein the anhydride of fatty acids is selected from the group consisting of myristic anhydride, palmitic anhydride, erucic anhydride, and heptanoic anhydride.

35. The method of any one of claims 22 to 24, wherein the functionalizing agent is succinic anhydride.

36. The method of any one of claims 22 to 24, further comprising a step iii) of adding an additive selected from the group consisting of a plasticizer an antibacterial agent, a flavoring agent, a coloring agent, a sweetener, and an antioxidant.

37. The method of claim 36, wherein said plasticizer is selected from the group consisting of glycerol, propylen glycol, and sorbitol.

38. The method of claim 36, wherein said antibacterial agent is selected from the group consisting of propionic acid, sorbic acid, and benzoic acid.

39. The method of claim 36, wherein said antioxidant is selected from the group consisting of butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT).

40. A method for manufacturing a gelatin composition for use in the preparation of dosage forms, said method comprising the steps of:

41. The method of claim 41 , further comprising at step ii) the addition of 0.5-15% (w/w of the composition) of a lipid to the negatively charged polysaccharide.

42. The method of claim 42, further comprising at step ii) the further addition of 0.5-10% (w/w of the composition) of an emulsifier to the negatively charged polysaccharide.

43. The method of any one of claims 40 to 42, wherein the polysaccharide is selected from the group consisting of alginate, hyaluronate, pectin, carrageenan, xanthan, and galactomanan or a combination thereof.

44. The method of any one of claims 40 to 42, wherein the polysaccharide is alginate.

45. The method of any one of claims 40 to 42, wherein the lipid is selected from the group consisting of fatty acids, preferably stearic acid, oleic acid and palmitic acid, mineral oils, vegetal oils, preferably canola oil, lin oil, soybean oil, and polycaprolactone.

46. The method of any one of claims 40 to 42, wherein the emulsifying agent is selected from the group consisting of ionic and amphoteric compounds.

47. The method of claim 46, wherein the emulsifying agent is selected from the group consisting of zwitterions, phosphatidylcholin, phosphatidylserine, phosphatidyl ethanolamine, and phsphatidylinositol, or a mixture thereof.

48. The method of any one of claims 40 to 42, wherein the gelatin is porcine gelatin, bovine gelatin or fish gelatin, obtained from either skin, bones or cartilage.

49. The method of any one of claims 40 to 42, wherein the functionalizing agent comprising a carboxylate group is selected from the group consisting of succinic anhydride, glutaric anhydride, maleic anhydride, isovaleric anhydride, diglycolic anhydride, and monochloracetic acid.

50. The method of any one of claims 40 to 42, wherein the functionalizing agent comprising an acyl chain containing group is selected from the group consisting of acyl chloride, anhydride of fatty acids, dodecenylsuccinic anhydride, nonenylsuccinic anhydride, and 2- dodecen-1-yl-succinic anhydride.

51. The method of claim 50, wherein the acyl chloride is selected from the group consisting of palmitoyl chloride, steroyl chloride, and myristoyl chloride.

52. The method of claim 50, wherein the anhydride of fatty acids is selected from the group consisting of myristic anhydride, palmitic anhydride, erucic anhydride, and heptanoic anhydride.

53. The method of any one of claims 40 to 42, wherein the functionalizing agent is succinic anhydride.

54. The method of any one of claims 40 to 42, further comprising a step iii) of adding an additive selected from the group consisting of a plastifier, an antibacterial agent, a flavoring agent, a coloring agent, a sweetener, and an antioxidant.

55. The method of claim 54, wherein said plastifier is selected from the group consisting of glycerol, propylen glycol, and sorbitol.

56. The method of claim 54, wherein said antibacterial agent is selected from the group consisting of propionic acid, sorbic acid, and benzoic acid.

57. The method of claim 54, wherein said antioxidant is selected from the group consisting of butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT).