Title:  Soft-gelatin capsule comprising S-adenosylmethionine and a method for producing the same

United States Patent:  6,759,395

Issued:  July 6, 2004

Inventors:  Rao; Canakapalli Bhaktavatsala (Tamil Nadu, IN); Chakrabarti; Prasanta Kumar (Tamil Nadu, IN); Ravishankar; Hema (Tamil Nadu, IN)

Assignee:  Orchid Chemicals & Pharmaceuticals, Ltd. (Tamil Nadu, IN)

Appl. No.:  020184

Filed:  December 18, 2001

Abstract

The invention provides a novel soft gelatin capsule comprising a fill material consisting essentially of S-adenosylmethionine (SAMe) salt disposed within an enteric coated soft gelatin film.

SUMMARY OF THE INVENTION

In accordance with the above and other objectives, the invention provides a soft gelatin capsule containing S-adenosylmethionine or its stable salts as active ingredients.

DETAILED DESCRIPTION OF THE INVENTION

Accordingly, after lengthy investigations and variations of materials and quantity ratios, the Applicant has developed a novel soft gelatin capsule containing SAME or its salts as active ingredients.

The invention provides a novel soft gelatin capsule comprising a fill material consisting essentially of S-adenosylmethionine (SAMe) salt disposed within an enteric coated soft gelatin film.

The fill material comprises a core of SAMe salt coated with lipophilic material, which is further provided an oily matrix, antioxidants and preservatives.

To counter and avoid the hygroscopicity and low pH problems of SAMe, the Applicant has chosen some of the more stable derivatives of SAMe, i.e. S-adenosylmethionine disulphate and monosulphate tosylate salts. These salts can be prepared by the synthetic route and are biocompatible. The method for preparation of these compounds is also easy.

The soft gelatin capsule of the invention essentially comprises SAMe or its salts as active ingredients, disposed within an enteric coated soft gelatin capsule.

A very essential aspect of the invention resides in the selection of the appropriate filling materials in quantity and ratios that ensure that SAMe is provided in an acceptable dosage form with greater bioavailability. Accordingly, the invention provides soft gelatin capsules of excellent stability and durability which are produced from ingredients, some of which are known, but have never before been combined in this specified form.

Preparation of Fill Material

As a first step, SAMe-disulphate monotosylate salt or monosulphate tosylate salt is coated or insulated with a lipophilic material. Typical examples of such material are stearic acid, carnuaba wax, beeswax, polyoxyethylene sorbitan monooleate, etc. Hydrogenated vegetable oils such as sterotex can also be used for the coating. In the alternative, fatty acid compounds such as cetyl alcohol, glyceryl monostearate, cetostearyl alcohol and glyceryl behanate can be used. These materials may optionally be diluted with dichloromethane or isopropylalcohol.

The substance selected for coating of SAMe-salt is one which is a non-irritant and non-toxic to the human body. Further, the compounds selected for coating are hydrophobic in nature. This coating or insulation protects SAMe salts from any direct exposure to moisture (from gelatin shell or environment) and preserves the integrity of the drug. The amount of SAMe salts in the capsule ranges from 425 mg to 440 mg depending on the assay potency, moisture content and overage.

The amount of the lipophilic material employed for coating SAMe salt may be 15 to 20% w/w. This particular range has been found to be most effective and advantageous, although the art recommends the use of 16% w/w.

The lipophilic material may be diluted with dichloromethane or isopropyl alcohol to achieve best results.

The ratio of the lipophilic material to the drug (SAMe salt) depends on various factors such as the amount of protection sought to be given to the salt and the in vitro dissolution of drug availability. The optimum drug: lipid fill material ratio is 5:1.

Once the salt is coated, it appears as a granular material. "Coating" as used herein means the drug is dispersed in the lipid matrix by conventional methods known in the art. Granules carrying the drug are obtained, which are eventually dried to remove all traces of the diluents, if used. The granules are milled to fine particles of uniform size, preferably 60 mesh to 250 microns.

The granules are suspended in an oily matrix composed of oils selected from soya oil, arachis oil, wheat germ oil, corn oil and rice bran oil.

The oils selected for the oily matrix should be inert, non-toxic, biocompatible, easy to handle, easily available and inexpensive. The oil chosen should also provide appropriate consistency to the lipoid fill material and stability in the final product. The oils recommended herein have been chosen with these criteria in mind.

The oily base acts as a viscosity enhancer. The granules in the oily matrix form a lipoid substance. If the viscosity is too high, the fill will face problem of smooth material transfer into the cavity of the capsule. If the viscosity is too thin, there will be loss of fill material due to continuous drip. The viscocity of the lipoid filler material may be adjusted so that it cannot be readily removed from the capsule with syringe at room temperature. This feature helps to protect against possible intravenous abuse of the drug and product tampering.

The amount of oil used is approximately 50-55% w/w of the total fill material used, although use of 53% gives best results.

Antioxidants such as ascorbic acid, may also be added to the blend to further protect the salt from degradation. Butylated hydroxy toulene NDGA and butylated hydroxy anisole may optionally be used as anti-oxidants. The amount of anti-oxidants in the blend may vary depending on the formulation, but the optimum amount may be 0.1% w/w. Additional materials such as preservatives, like paraben may also be added to the fill such material. The fill material thus prepared is a soft viscous mass in a lipoid matrix, which is non-aqueous.

Preparation of Soft Gelatin Capsule

The method of preparing a soft gelatin capsule comprising SAMe, comprises the steps of:

a. coating SAMe salt with a lipophilic material to obtain granules,

b. coating the granules obtained in step (a) with an oily matrix, antioxidants and preservatives to form a lipid suspension,

c. disposing the lipid suspension within a soft gelatin film, and

d. providing the soft gelatin film with an enteric coating to obtain an enteric coated soft gelatin capsule.

The SAMe-salt encapsulated form according to the invention includes SAMe-salt formulation disposed within an enteric coated soft gelatin film. Since the capsule fill consists of lipid suspension, the drug delivery vehicle is a one piece soft gelatin capsule, which is sealed along the seamline. The soft single-piece capsule is preferred as compared to the conventional two-piece capsule, since the soft single-piece capsule does not require additional sealing of the capsule halves as required for the 2-piece capsule. The soft single-piece capsule is also less prone to product tampering and contamination.

The soft gelatin capsule should be immediately covered, protected from the environment and water. The Applicant tried many methods such as encapsulating with hard two piece capsule but failed in their attempts. However, after much trial, the Applicant thought of encapsulating SAMe in the soft gelatin capsule and have been able to achieve this. Once done, there is a guarantee that SAMe will not degrade or be exposed to moisture or other adverse conditions.

It is not easy to develop and produce soft gelatin capsules, under the state of art as such capsules are surrounded by several economic and technological problems. The problems are encountered especially when production of these capsules on commercial scale is attempted. The process technology for manufacture of soft capsules on a large scale are complex. Some processes impose the burden of disposal of net wastes. The invention uses cheap and commonly available materials and does not pose any problem of disposal of the waste.

However, the soft gelatin capsules of the invention are easy to manufacture and can be produced without great expenditure on equipments and production facility.

During the formation of the gelatin capsules, capsule wall material (film) and the fill material are fed into the equipment. The coating or wall material or film, and the fill material are led via tubular jets and thus, seamless soft gelatin capsule of appropriate shape and size are formed.

In developing the soft gelatin capsule of SAMe, it must be recognized that the capsule comprises of the formulation as well as the gelatin film used to encapsulate the formulation. As such, not only is the filled SAMe formulation which is critical to produce the desired bioavailability characteristics but the gelatin film is also critical as it must be compatible with SAMe formulation. One skilled in the art would be aware of the potential fill-shell interactions which could result in both physical and chemical capsule instability. Accordingly, the gelatin film or capsule wall materials utilized to form the capsule for the SAMe dosage form is also critical to the present invention.

For formation of the wall of the soft gelatin capsule, one of the main ingredients of the wall of the capsule is gelatin which is used in an amount of 40% to 60% w/w. Usually gelatin and glycerine are present in different ratios ranging from 1:1 to 1:0.4 depending on the hardness desired for the capsule.

A plasticizer such as PEG 400, or a non-crystallizing solution of sorbitol may be used. If sorbitol is used alone as plasticizer, the amount may be 10 to 20%. If used in combination with other plasticizers, or if any other plasticizers are opted for, the amount may be 8 % to 10% w/w.

Softening agents selected from glycerol, glycerine, triacetin, sorbitol, sorbitan anhydrides and mannitol in the range of 10% to 15% are advantageously added to soften the wall of the capsule. Furthermore, other non-traditional ingredients may be used to plasticize the gelatin such as polyethylene glycol 200 (PEG 200). The amount of the plasticizer used does not exceed 25 to 30%.

The capsule wall or wall of the film may also include other suitable additives such as preservatives and/or coloring agents which commonly utilized to impart a specific characteristic such as color or look to the capsule. As is known, certain colours are specific for specific markets. A color like iron oxide yellow is recommended for the gelatin capsule of the invention. Color may be imparted to the gelatin shell using appropriate dyes. The amount of the colour material may be in the range of 0.25% to 0.5% w/w.

Pharmaceutically acceptable preservatives which may also be included in capsule wall include, for example, methyl and propyl parabens. The amount of the preservatives added may be in the neighbourhood of 0.1 w/w to 0.2% w/w. The preservatives added also act as anti-microbial agents.

Opacifiers, such as titanium dioxide and/or iron oxides; may also be employed to render the capsule opaque. The opacifiers may be present in an amount of 0.2 to 0.5% w/w.

In soft gelatin capsules the gelatin ribbon (from proper gelatin paste formulation) is wrapped around pre-cooled drum which subsequently encases the liquid fill material through sealing along seamline and arrested in appropriate die rolls. Generally, in soft gel capsules formulation, the fill material is non-aqueous and either lipid form or homogenous suspension or emulsion form of the lipoid system. So, there is interaction between fill material and shell. In the present case, the fill material is totally lipid matrix, so interaction is absolutely not possible with the shell.

The thickness of the gelatin capsule may vary depending on the type of the formulation and medicament conditions. However, for the capsule of the present invention, thickness of 1.1 mm is preferred, although the thickness may be in the range of 0.9 mm to 1.1 mm.

The capsule after preparation are dried at 15% RH for a period of 48 hrs at 20 to 25^oC. Subsequently the capsule is provided with an enteric coating of methylacrylic acid copolymer.

Pharmaceutical dosage forms are often provided with a coating primarily to protect the acid-sensitive drug from the stomach environment, as it is likely to cause irritation. These coatings are referred as `enteric coatings`. The coating is however, soluble in the alkaline environment of the intestine, in which the drug in question, i.e. SAMe is sought to be released. The enteric coating also serves a variety of other purposes such as rendering the dosage more palatable, improving appearance, extended release of drug, protection against moisture etc.

The enteric coating is pH dependent. Enteric coating polymer of acrylic acid co-polymer origin (Eudragit L100 55) or cellulosic polymer (HPMCP-55). The enteric coating starts dissolving on and from 5.5 (anterior part of intestine). So after ingestion of capsule for at least 2 hours, the enteric coating will remain intact. Coating is applied through spray coating device in auto-coater. Enteric coating thickness will be 250-350 microns.

The thickness of the enteric coating has been optimised considering food effects, transit time, gastric environment, etc. The enteric coating material is prepared using conventional methods such as reported in U.S. Pat. No. 4,287,221, which is incorporated herein by reference.

The enteric coating may comprise materials such as hydroxypropylmethyl cellulose phthalate (HPMCP), hydroxypropylmethyl cellulose succinate (HPMCS) and carboxymethyl cellulose (CMEC), methylacrylic acid copolymer etc. The Applicant unexpectedly found that when hydroxypropylmethyl cellulose phthalate (HPMCP) and methylacrylic acid copolymer are used for enteric coating, the bioavailability of soft gelatin capsules is increased.

More specifically, the material of the enteric coating and the thickness of the soft gelatin capsules of the invention are designed to keep the capsule intact for a period of at least about 2 hours, after oral administration. The lag time or delay in release of the pharmaceutically active ingredient is 2 hours after contact with gastric juices of the stomach.

In the present invention, applicant found that glycerin could be advantageously used in the dosage form of the invention. The Applicant unexpectedly found that glycerin acts as a humectant when used in the invention. Humectants are hygroscopic ("water-pulling") substances that are incorporated to promote retention of moisture. As such, the amount of gelatin formulations recommended in the invention provide the necessary physical and chemical stability required for use with the fill material. In fact, in the capsule of the present invention, gelatin is used as one of the main ingredients.

The fill material is introduced into the gelatin capsule prepared as above. For the invention, manufacturing conditions must be maintained to ensure that the capsule environment is properly maintained with respect to temperature and relative humidity.

In a preferred embodiment, the soft gelatin capsules of the invention are given oblong shape. The Applicant has found that straight edges or unbowed edges may cause capsules to stick to each other and form `twins`. Twinning of capsules is also caused if the coating on the capsules is tacky. Twinning often occurs at the time of drying of the capsules. The capsules prepared according to the present invention do not suffer from this problem since period raking is undertaken at the time of capsule manufacture. Also the temperature and moisture conditions are maintained at 15 to 17^oC. and RH of 16-20%

For these reasons, the capsules of the invention are thoroughly dried and the coating thereon is such as to avoid the aforesaid problems encountered in the prior art.

Advantages of the Capsule Form of SAMe Over the Tablet Form:

The capsules of the invention are stable and durable and can be used for at least 2 years from the date of its manufacture. Ideally, the capsules should be stored at 8 to 15^oC., although they can tolerate temperatures as high as 25^oC. The soft gel capsules show better efficacy in terms of enhanced absorption and availability in the body.

SAMe tablets often get softened and discoloured (even sometimes with leaching of active moiety) when exposed at 25^oC. and ambient relative humidity conditions. Unlike tablets, SAMe soft gel capsules do not show such degradation when exposed under similar condition.

Tablet dosage form generally incorporates the active moiety in solid matrix which may not be favourable condition for better absorption and availability of the active moiety (SAMe here) in the body.

In the present invention, SAMe is formulated in liquefied lipid matrix through which absorption and availability of the active moiety (SAMe) in body is enhanced. SAMe being hygroscopic and vulnerable towards moisture atack, the technique of wax encapsulation followed by dispersion in lipid matrix (adopted in this invention) confer better stability. Organoleptically, SAMe in soft gel delivery system looks more elegant and convenient over the tablet dosage form.

Claim 1 of 30 Claims

What is claimed is:

1. An enteric-coated soft gelatin capsule with fill material comprising a core of S-adenosylmethionine salt selected from the group consisting of a S-adenosylmethionine monosulphate tosylate salt and a S-adenosylmethionine disulphate tosylate salt, said salt being coated with lipophilic material, an oily matrix, antioxidants and preservatives, said fill material being disposed within a soft gelatin film.

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