MXPA97004849A - Filling material for a phase of pharmaceutical dosage of soft gelatin, which contains an antiflatule - Google Patents

Abstract

The present invention relates to a semi-solid filling material for a soft gelatin capsule, which contains a therapeutically effective amount of an antiflatulent. The semi-solid is sufficiently viscous so that it can not be easily expelled at the ambient temperature of the capsule, with a syringe

Description

FILLING MATERIAL STOP FORMAL PHARMACEUTICAL DOSAGE OF BLACK GELATIN, WHICH CONTAINS AN ANTIFLATULENT FIELD OF THE INVENTION The present invention relates to a soft gelatin capsule, filled with a sernisolide or containing an effective therapeutic treatment of a + alen + o. This invention is also related to the US patent applications No, serial 08 / 366,945, filed on December 9, 1994, entitled "Soft gelatin dosage form"; Serial No. 08/366,!!, Filed on December 29, 1994, entitled "Gelatinizing agent for pol and ilenglicol"; Serial No. (Proxy case NCP-155), presented on, entitled "Filling material for pharmaceutical dosage form of soft gelatin" and serial No. (Case of the attorney MCP.166), presented on, entitled "Form of soft gelatin dosage of multiple phases ", all of them assigned to the same cause as the present invention, and all of them incorporated herein as reference.

BACKGROUND OF THE INVENTION In recent years, soft gelatine capsules or soft elastic gelatin capsules have become a popular dosage form for the oral delivery of therapeutic agents, especially for over-the-counter pharmaceutical products. These capsules are typically filled with a liquid containing the active ingredient. Due to its soft and elastic nature, some patients see these capsules as easier to swallow * than tablets or hard gelatin capsules. Since the dosage form is generally swallowed, it is not necessary to flavor or otherwise mask the commonly unpleasant taste of the pharmaceutical product. Soft gelatin capsules are also preferred to loose liquids because they are easier to transport and avoid the need for the patient to leave a prescribed amount of liquid before taking the dose. The filling material used in a soft gelatin capsule generally contains a pharmaceutical product dissolved or dispersed in a carrier that is compatible with the capsule wall. In addition to liquids, U.S. Patent No. 4,935,243 to L. Bordan and co-inventors suggests that the filler waste may take the form of a sernisolide, a solid or a gel. Conventional tablets or pills containing an active ingredient are examples of solid fillers which can be encapsulated in a soft gelatin capsule. Sinisolide filler materials (dispersions) are discussed in U.S. Patent No. 4,486,412, to D. Shan and co-inventors. A filler material containing an orally administered antacid salt, which is dispersed in a liquid carrier without water, which contains a higher proportion of one or more polyalkyl glycols and a minor proportion of a polyol of 2 to 5 carbon atoms, such as propylene glycol or glycepne. The carrier forms a stable dispersion of the antacid salt and covers the antacid particles, thus rendering them non-reactive with the soft gelatin capsule wall. The dispersion may also contain a loxane polis as a flatulence relieving agent, such as ethicone, as optional ingredients. Such optional ingredients comprise about 0 to 5% on weight of the total dispersion. US Pat. No. 4,708,834 to Cohen and co-inventors suggests a controlled release dosage form comprising a soft gelatin capsule enclosing a gel-bonded, soluble or water-dispersible maize. The filler material comprises an aqueous solution or dispersion of a polys'capdo gum, the pharmaceutically active ingredient and, optionally, an alcohol. The liquid filling is introduced into a soft gelatin capsule containing a cationic gelling agent, which gels the liquid filling after it has been incorporated into the capsule shell. The alcohol used in the filling includes liquid polyethylene glycols, lower alkanols, polyols of 2 to 4 carbon atoms, and mixtures thereof.

U.S. Patent No. 5,071,643 to M. Yu and co-inventors also described the use of pol letilenyli coles (PEG) as a filler in soft gelatin dosage forms. PEGs having an average molecular weight between 400 and 600 are preferred for liquid fillings; between 800 and 10,000 for fillings are isolidos and between 10,000 and 100,000, for solid fillings. ernmgt on 's Pharrn ceutical Sciences, 18a. edition, chapter 83, pages 1539-40 (1990) reports that the gelling agents used to form gels for pharmaceutical and cosmetic products include sodium alginate and anoxia. The publication of TCP No. UO 91/07950 discloses a soft gelatin capsule or two-piece hard gelatin capsule, containing benzodiazepine dissolved or suspended in a gel. The gel contains, by weight, at least 53% polyethylene glycol 600, at least 4% pol letilengl col 4,000 or 6,000; and at least 21% polyethyleneglycol 600-4,000. This gel filling can not be easily expelled with a syringe at room temperature and, therefore, avoids the reported abuse of liquid-filled capsules by ravenous drug abusers. Antifatlants are typically incorporated in compressible tablets, by mixing oil-like substances, such as sirketone, with normal excipients for tabletting, before forming the tablets. U.S. Patent No. 5,073,384, to Valentine and co-inventors, discloses a suitable tablet-forming composition, comprising simethicone and a high-water soluble agglomerate. It is reported that the resulting combination flows freely and possesses activity desspúmame. Hungarian patent No. 203,477, published on January 28, 1991, discloses a solid antifiatulent dispersion containing poly (dimethylsiloxane) as a dispersed phase in a water-soluble carrier, the dispersion also contains a rnacromolecular auxiliary substance, network forrnadora and / or an interlayer, viscosity enhancer, such as polyvinyl chloride, polyacrylic acid or polyvinylpyrrolidone and / or inorganic solidifying agents, such as calcium phosphate, calcium sulfate serihydrate or calcium di-phosphate. Example 1 reports a solid mass containing 60 g of polyethylene glycol 6,000, 15 g of polyvinyl chloride and 25 g of activated diketone (sirneticone) which can be ground and filled with solid gelatin capsules or can be formed table as. French patent application No. 2,624,012, published on June 9, 1989, relates to a soft gelatin capsule containing a suspension or solution of doral hydrate in an inert carrier of high viscosity. Suitable carriers for use in the capsule include oily solvents of mineral or vegetable oil, such as olive oil, peanut oil, paraffin oil, petrolatum oil or mixtures of vain oils; a liquid ilicon, such as dimethicone or sirneticone; a glycol polymer, such as polyelenol col 600, 800 1200; and a glycol, such as ethylene glycol, propylene glycol or glycol ol. . Siringtonone has been incorporated into oral syrup or liquid clar-a formulations. 0. Banga and coauthors, in Incorporation of Sirnethicone i nto Syrup or Clear Base l.iquid Orai, Drug Development and Industrial Phartnacy, 15 (5), pages 691-704 (1989), two have a variety of vehicles for sirketone, but reports that the best results were obtained with CARB0P0L resins (neutralized R (carboxypoly rnet). ) in combination with glycepna and propylene glycol There is a need for an isophilic filling material containing an antiflatulent, suitable for use in the production of soft gelatin capsules.The filling material must be sufficiently viscous to prevent it from being expelled. of the capsule cover with a syringe to minimize the potential for tampering or falsification of the product.The filling material should also not affect the antifouling properties of the antifouling.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides a sinisolide filler material for a soft gelatin capsule comprising a polyalkylene glycol and an antifiattulent. The semisolid is sufficiently viscous so that it can not be expelled at room temperature from the capsule with a syringe, which preferably has a 16 gauge or smaller needle. In another embodiment of the present invention, the filler material has an oxidized viscosity of 10,000 to 2,500,000 centipoise (cP). The semi-solid filler material has no detrimental effect on the anti-sputtering activity of the anti-fuming agent, such as sunethicone.

DETAILED DESCRIPTION OF THE PREFERRED MODALITIES The present invention relates to a sernisolide containing an anti flatulent for filling a pharmaceutical dosage form of soft gelatin capsule. Sermsolide can also be used to fill a two-part hard gelatin capsule. The viscosity of the semisolid is also controlled so that it can not be easily removed from the capsule with a syringe at room temperature. This aspect helps to protect against possible intravenous abuse of the drug, as well as against the violation or alteration of the product. As used in the present description, a seriolide is a system of at least two constituents consisting of a condensed mass that encloses a, and is interpenetrated by, a liquid. The semi-solid filler material is sufficiently viscous so that an appreciable amount, less than about 1, preferably less than about 0.5 g, can not be expelled at room temperature with a syringe having a 16 gauge needle. or less. The sernisolide preferably has a viscosity at 25 ° C of about 10,000 to 2,500,000, preferably about 400,000 to 2,000,000 centipoise (cP). The solid of the present invention contains a polyalkylene glycol. Suitable polyalkylalkylene glycols are polyethylene glycol (PEG) having an average molecular weight of about 400 to 20,000, preferably about 400 to about 3,350. The solid usually comprises, by weight, about 30 to 70, preferably about 40 to 60, percent of p > olialqu? lengl? col. Unless stated otherwise, the percentages quoted here are by weight, with respect to the total weight of the material of i > Semi-solid, that is, both the solid nemi and the PEG mixtures of various molecular weights can also be used in the semi-solid filler material of the present invention. The mixtures will generally contain low molecular weight PEG, having an average molecular weight of about 600 or less, mixed with high molecular weight PEG, having an average molecular weight of from more than 600 to about 10,000, in amounts that produce an authentic serni. Preferably said mixtures contain about 0.25 to 5% PEG of low molecular weight and about 45 to 50% of PEG of high molecular weight. In addition to the liquid polyalkylene glycol, the semisoli may contain one or more auxiliary agents, forming solid serums, in the amount shown (percentage by weight of 5 semi-liquids):% Component 0.05-10 propylene glycol 0.05-15 Plurol stearic ( 6- poly-l-gylceryl distearate) 0.05-10 Peceol (glycerol oleate) 0.05-5 Hydroxypropylcellulose NF (KLUCEL HF; leno weight: 1, 150,000) Sernisolide may contain from 0 to about 10% and < - The antiflatulent or is present in the dosage form n a therapeutically effective amount, which is an amount -. which produces the desired therapeutic response by oral administration, and which can be easily determined by one skilled in the art. In determining such quantities, one must take into consideration the particular compound being administered, the bioavailability characteristics of the compound, the dose regimen, the age and weight of the patient and other factors. Suitable ntiflatulents for use in the invention include simethicone and dimetone. In general, the ant f latulent? comprises from 30 to 7, preferably from 40 to 60 weight percent, approximately, of the total semi-solid filler material. The purge time of the sernisolide filling material containing the anti-latulent preferably is less than 15, more preferably, less than 9 seconds. Pharmaceutically acceptable excipients may be included in the semi-fluid filler material <; -, (ales . preservatives, for example, methyl- or propylparaben, coloring agents, sabotagers, lubricants, flow improvers, antioxidants, humectants (glycerin), surfactants, plasticizers, fillers and other compounds, agents and components that produce a attractive final product. In a preferred embodiment, the sernisolide filler for a soft gelatin capsule containing 547 ng / ml of sirketone comprises, by weight, about 40 to 60 percent of sirketone, about 1 to 3 percent polyethylene. or id glycol having an average molecular weight of 300 to 400, and about 40 to 60 percent of solid polyethylene glycol, which has an average molecular weight of 1,450 to 4,600. This semsolid preferably has a viscosity of about 90,000 to 1,000,000 cp at 25 ° C, a time of de-frustration of about 8 seconds, approximately (when measured by the USP method described below) and a possibility of syringe manipulation of less than 0.5 and (when measured by the method described below). The filler material of the present invention can be used in commercially available soft gelatine capsules, such as those that can be obtained -Rially of R. P: Scherer or Banner Pharmacaps. You can use different sizes, shapes and colors to accommodate different levels of active ingredients. The walls of the capsules have a substantially translucent or clear appearance. When the filling material of the present invention is introduced into the capsule and forms a sernisolide, the resulting dosage form has an opaque white appearance; or dyes can be added to have any desired color. The filling material is heated before being cary in the capsule, because it is extremely viscous at temperatures below 40 ° C. You can handle soft gelatin capsules filled with air, filled with a syringe. The hot id filling is loaded into a syringe. The needle of the syringe is used to prick one end of the soft gelatin capsule, so that the approximate amount of the filling material can be injected manually. The capsule is to be cooled with the filling material. You can also introduce the filling material into the soft gelatin capsule w ti. or encapsulation equipment that is known in the art, such as that described in U.S. Patent No. 4,028,024 to Moreland, which is incorporated herein by reference. As previously described with the hand filling technique, the filling should be maintained at about 40 ° C during the filling operation, so that it flows easily into the capsule.

Accordingly, the filling can be stored in a jacketed container and can be transported through a thermostat-controlled feeding tube to the encapsulation equipment.Specific embodiments of the present invention are illustrated by means of the These examples are not confined to the specific limitations indicated in these examples, but rather to the scope of the attached indications, unless otherwise indicated, and the proportions given below are in p. Regarding the total composition, the viscosity was measured in the following examples using a Rheornetrics 8400 Fluid Spectrometer at 25 ° C. Using a 25 mm parallel plate and a constant tension of 10%, frequency sweeps were recorded. viscosity at a frequency of 1.0 radian per second The dehussing test was carried out in the following examples using the specifications and The procedures of the Pharmacopoeia < * the United States 23 rev., íhe National Formulary, 18a. edition. The skimmer-a solution consisted of 1% octoxmal-9 and 0.0005% FD8C Blue # 1 in water. The test equipment included a weight-action shaker with a radius fixed at 13.3 A0.4 cm (measured from the center of the arrow to the center of the bottle). An equivalent of 20 rng of simet-1cona was transferred to a jar containing 100 ml of sputtering solution, previously heated to 37 ° C. The jar was covered and shaken at an arc of 10 ° to one.A 300 ± 30 strokes / minute, for 10 seconds The one that took a lot of foam-free liquid to appear was recorded. The USP limit for the TMN is 15 seconds. The syringe handling test was carried out in the following examples to measure the ability to handle said formulation, within a period of time. 1 ado. This test was used as a measure of ia r *? A to the violation. Syringes of 10 c with 16 gauge needles, 3.81 cm long, were used. The syringe was placed in the formulation, pulled up the plunger and held for 10 seconds. The weight of the material brought to the syringe was recorded.

EXAMPLE 1 This example describes semi-solid materials of the present invention containing 547 mg / ml simethicone. The following samples were prepared: Quantity (% w / w) Component ABCDE PEG 1450 50.0 __ __ PEG 3350 - 50.0 - - PEG 4600 - - 50.0 - PEG 8000 __ - - 50.0 NA (Dow .u? Ni ng) 50.0 50.0 50.0 50.0 50. p Samples were prepared: 1) PEG was weighed. r > The PEG was melted and stirred on a hot plate, regulated at 80 ° C until it was clear. slowly added the sirketone and stirred at high speed for about 20 minutes. 4) It was removed from the heat and allowed to cool without agitation. The resulting samples were opaque sernisolids.

EXAMPLE 2 This example describes semi-solid filling materials of the present invention containing 547 mg / rnl of sirketone. The following samples were prepared: Quantity (% w / w) Component A B C D PEG 400 0.5 0.5 0.5 0.5 PFG 1450 49.5 PEG 3350 49.5 PEG 4600 49.5 PEG 8000 49.5 Sirne icona (Dow Corning) 50.0 50.0 50.0 50.0 The samples were prepared as follows: 1) The PEGs were weighed. 2) The PEG was melted and agitated on a hot plate, regulated at approximately 80 ° C, until they were clear. 3) Ethicone was added slowly and stirred at high speed for about 20 minutes. - * • removed from the heat and allowed to cool without agitation. The resulting ones were opaque sem solids.

EXAMPLE 3 This example describes semi-solid filler materials of the present invention containing 547 rng / rnl of sirketone. The following samples were prepared: (Quantity (% by weight / weight) Component 0 B 0 D PFG 400 3.0 3.0 3.0 3.0 PEG 1450 47.0 PITG 3350 - 47.0 PEG 4600 - - 47.0 PEG 8000 - - - 47.0 Jirneticona (Dow Corning) 50.0 50.0 50.0 50.0 The samples were prepared using the procedure of Example 2. The resulting samples were opaque semisolid.

EXAMPLE 4 This example describes a filling material of the present invention, which contains 547 rng / rnl of itself ", \. The next sample was prepared. Component Quantity (% weight / weight) PEG 400 2.5 PEG 3350 47.5 Simethicone (Dow Corning) 50.0 Samples were prepared using the procedure of Example 2. The resulting sample was an opaque semi-solid. The following summarizes the results of the sample tests of examples 1 to 4 and the control of sirne icona: Handling with de-Viscosity Time Example syringe (g) foaming (sec) (cP) LA 0.047 11 3,009,000 IB 0.091 5 1,420,566 1C 0.1.80 9 331,700 LD 0.216 5 213,420 ) E 0.300 8 9.069 2B 0.054 6 2,856,000 2C --- - 2D 3A 3B 0.039 10 301,000 3C 3D 0.165 7 116.350 4 0.347 6 1,025,633 Sirneticona 1.675 9 612 (Dow Corning) In the case where multiple tests were performed with the same formulation, the above data are an average of the values measured for the formulations. The semisolids of the present invention have despunation times equal to or faster than the ethicone control. Traditionally, the syringe handling of the semi-solids of the present invention was significantly less than the sirketone control and the desorption times were higher than, or substantially equivalent to, the methicone control.

EXAMPLE 8 F r o o p e o r p a n d a n d a n d a n d a n a l a l a l a b a l a b a l a n a l a n a l a n a l a tio n s a n d a n d a n d a n d a n d a n d a n d a n d a n d a n d a n d a n d a n d a n d a n d a n d a n d in l a n d of simet icone The following sample was prepared: Component Quantity (% weight / weight) PEG 400 2.5 PEG 3350 47.5 Sime ti cona (Dow Corning) 50.0 The sample was prepared as follows: "^ or the PEGs melted and stirred on hot plate, regulated at about 80 ° C. 3) Simethicone was slowly added and stirred at high speed 4) It was removed from the heat and allowed to cool The resulting formulation was an opaque semiflush that had a dehusking time of about six seconds and a viscosity of 3, 000,000 cp. The semisolLdo was heated so that it flowed and then filled with hydrophobic and hydrophilic soft gelatin capsules, as follows: 1) The cylinder of a 10 cc syringe was filled with the simetone formulation, without the needle. 2) A 16 gauge needle was attached and placed inside a soft gelatin capsule filled with air, previously weighed. 3) A dose of 125 g of sirnet cona was carefully introduced into the air-filled capsule with the syringe. 4) The upper end of the capsule is sealed with a lime scale plate. The resulting soft gelatin capsules an opaque white appearance. Various modifications may be made to the above-described embodiments without departing from the spirit and scope of the present invention.

Claims (29)

NOVELTY OF THE INVENTION CLAIMS

1. A pharmaceutical composition, characterized in that it comprises: a semi-solid comprising a polyalkylene glycol having an average molecular weight of about 400 to 20,000; and a therapeutically effective amount of an anti-free agent, disposed in the sun.

2. The composition according to claim 1, further characterized in that the polyalkylene glycol is polyethylene.

3. The composition according to claim 1, further characterized in that it has an approximate viscosity of 10,000. 2,500,000 centipoises at 25 ° C.

4. The composition according to claim 1, further characterized in that it comprises adi citonal semioid forming auxiliary agents, selected from the group consisting of propylene glycol, 6-d-stearate polyglyceryl, glycerol oleate and hydroxypropylcellulose.

5. The composition according to claim 1, further characterized in that it comprises, by weight: about 30 to 70 percent, of polieti lengli col; and from 30 to 70 percent, approximately, of antifiatulent.

6. The composition according to claim 1, further characterizes as co-co of about 0.25 to 5 percent of a polyethylene glycol having an average molecular weight of 600 or less, and about 45 to 50 percent of a polyethylene glycol having a molecular weight of from 600 to 10,000, by weight of the composition.

7. The composition according to claim 1, further characterized in that it has a defoaming time of about 15 seconds, approximately.

8. The composition according to claim 1, further characterized because it has a possibility of manipulation with syringes of 0.5 and.

9.- The composition in accordance with the reivmdica-, also characterized because it is selected the lactose ..ic group consisting of simethicone and dimethicone.

10. The composition according to claim 9, further characterized in that the anti-flatulent is sunet icoite.

11. The composition according to claim 1, further characterized in that it comprises, by weight: about 40 to 60 percent, polyethylene glycol (jue has an average molecular weight of 400 to 3,350, and 40 to 60 percent

12. The composition according to claim 11, further characterized in that it has an approximate viscosity of 400,000 to 2,000,000 centipoise at 25 ° C.

13. The composition of the entity with the claim cion L, characterized furthermore because it comprises, by weight: from 40 to 60 percent, approximately, of simet cona; about 1 to about 3 percent of polyethylene glycol having an average molecular weight of about 300 to 400; and from 40 to 60 percent, approximately, of polyol and lecithol having an average molecular weight of about 1,450 to 4,600.

14. The composition according to claim 13, further characterized in that it has a viscosity of 900,000 to 1,000,000 centipoise, approximately 25 ° C, a de-purification time of about R seconds and a possibility of handling with syringe less than about 0.5 g.

15. A pharmaceutical dosage form, characterized in that it comprises: a gelatin capsule shell, filled with a senisolide comprising a polyalkylene glycol and a therapeutically effective one of an antiflatulent.

16. The dosage form according to claim 15, further characterized in that the polyalkylene glycol is polymelanic.

17.- The form of twoLS in accordance with the - claim 15, further characterized in that the semi-solid has an approximate viscosity of 10,000 to 2,500,000 centipoises, at 25 ° C.

18. The dosage form according to claim 15, further characterized in that the solid will comprise additional auxiliary agents forming solid solids, selected from the group consisting of propylene glycol, 6-d? Polyol cerol stearate, glycerol oleate and hydroxypropyl cellulose.

19. The dosage form in accordance with the re-infection 15, characterized furthermore because it comprises, by weight: about 30 to 70% of polyethylene glycol.; and about 30 to 70 percent of the antiflatulent.

20. The dosage form in accordance with section 15, c also acted because it comprises, in , J: from 0.25 to 5 percent, approximately, of a polyethylene glycol having an average molecular weight of 600 or less; and about 45 to 50 percent, of a letile glycol pol that has an average molecular weight of more than 600 to around- 10,000.

21. The dosage form according to claim 15, further characterized in that the senisolide has a defoaming time of less than 15 < seconds, approximately.

22. The dosage form according to claim 15, further characterized in that the semisolid has a possibility of handling with a syringe of less than about 0.5 g.

23. The dosage form according to claim 15, further characterized in that the anti-lactose titer of the group consisting of sirnet icone and dirneticone is selected.

24. - The dosage form according to claim 15, characterized by adornas because the anti flatulent is sirnet icona.

25.- The dosage form in accordance with the 5 claim 24, characterized in that it comprises, by weight: about 40 to 60 percent polyethylene glycol, having an average molecular weight of about 400 to about 3,350; and about 40 to 60 percent, of simethicone.

26.- The dosage form of conformity is 10 to 25 claim 25, characterized by adornas because it has an approximate viscosity of 400,000 to 2,000,000 centipoises, at 25 ° C.

27. The dosage form according to claim 15, further characterized in that it comprises, in weight: about 40 to 60 percent, of sirnet icone; from 1 to 3 percent, suitably, of polyethylene glycol, which has an average molecular weight of 300 to 400, approximately; and about 40 to 60 percent, of polyethylene glycol having an average molecular weight of 1.450 to 4,600, approximately.

28. The composition according to claim 27, further characterized in that the semi-solid has an approximate viscosity of 900,000 to 1,000,000 cp at 25 ° C; a defoaming time of less than 8 seconds, Or: Approximately, and a possibility of syringe manipulation of about 0.5 g.

29. - The dosage form according to claim 15, further characterized in that the cover is a soft gelatin capsule.