MXPA97004846A - Dosage form of soft gelatine, of phases multip - Google Patents

Abstract

The present invention relates to a dosage form containing a common shell of polymeric material. The enclosure contains multiple phases of semi-solid filling materials containing active ingredients

Description

FORM OF DOSE OF BLACK GELATINE, OF MULTIPLE PHOSES COMPO OF THE INVENTION The present invention relates to a gelatin capsule having discrete phases or regions of a solids filler material containing an active ingredient. This invention is also related to U.S. Patent Applications Serial No. 08 / 366,945, filed December 29, 1994, entitled "Forme of Pharmaceutical Dose of Soft Gelatin"; Serial No. 08 / 3F) fi, 271, filed on December 29, 1994, entitled "Gelling agent for polyethylene glycol"; Serial no. (Case of attorney-in-fact MCP-155), filed ol, entitled "Filling material for pharmaceutical dosage form of soft gelatin" and serial number (Case of attorney MCP.160), presented on, entitled "Material of filling for pharmaceutical dosage form of soft gelatine containing an anti flatolent ", all of them assigned to the same cause as the present invention, and all of them incorporated herein by reference.

BACKGROUND OF THE INVENTION In recent years, soft gelatin capsules or soft elastic gelatin capsules have become a popular dosage form for the oral delivery of therapeutic agents, especially for veni-free 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 sabotage or otherwise mask the often unpleasant taste of the mac product. It is also preferred the capsules of - Soft label to loose liquids because they are easier to transport and avoid the need for the patient to measure a prescribed amount of liquid, before dosing. 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. Borkan and co-inventors suggests that the filler material can take the form of a sernisolide, a solid or a gel. Conventional tablets or pills containing an active ingredient are examples of solid fillers that can be encapsulated within a soft gelatin capsule. The fillers are ísólidos (dispersions) are discussed in US Patent No. 4,486,412, i). fj a and co-inventors. A filling 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 polyalkylene glycols and a minor proportion * 5 of a polyol of 2 to 5 carbon atoms. carbon, such as propylene glycol or gil cerine. The carrier forms a stable dispersion of the antacid salt and covers the antacid particles, thus making them unreactive with the wall of the soft gelatin capsule. The dispersion can also contain a polysiloxane as a flatulence relieving agent, such as co-or phenylketonone, as optional ingredients. Said optional ingredients comprise about 0 to 5% by weight of the total dispersion. U.S. Patent No. 4,708,834 to Cohen and 1 * 5 co-inventors suggests a controlled dose controlled dosage form comprising a soft gelatin capsule enclosing a gelled polymerase matrix, soluble or dispersible in water. The filler material comprises an aqueous solution or dispersion of a polysaccharide 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 filler 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 describes the use of polyethylene glycols (PEG) as a filler in soft gelatin dosage forms. PEGs that have an average molecular weight of between 400 and 600 are preferred for liquid fillings, between 800 and 10,000 for semi-solid fillings and between 10,000 and 100,000 for solid fillings, Remington's Phrnaceutical Sciences, 18th edition, Chapter 83, pages 1539-40 (1990) reports that gelling agents used to form gels for pharmaceuticals and cosmetics include sodium alginate and t -ethanol amine.TCP publication No. UO 91/07950 describes a gelatin capsule shell soft or 5-piece hard gelatin containing benzodiazepine dissolved or suspended in a gel The gel contains, by weight, at least 63% polyethylene glycol 600, at least 4% polyethylene glycol 4,000 or 6,000; at least 21% polyethylene glycol 600-4,000.

This gel filling can not be easily expelled with a syringe at room temperature and, therefore, avoids the reported abuse of capsules filled with liquid by abusers of intravenous drugs. Antifatlants are typically incorporated into 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 Valentme and co-inventors, discloses a composition suitable for forming * tablets, which comprises simethicone and a water soluble rhnaltodextrin agglomerate. and reports that the resulting combination flows freely and possesses defoaming activity. Hungarian patent No. 203,477, published on January 28, 1991, discloses a solid, flammable dispersion containing poly (d? Methyl? Loxane) as a dispersed phase in a water soluble carrier. The dispersion also contains a rnacromolecular, network forming and / or interlacing, viscosity enhancing auxiliary substance, such as polyvinyl chloride, polyacrylic acid or polyvinylpyrrolidone and / or inorganic solidifying agents, such as tpcalcium phosphate, sulfate sulfate hydrate. of calcium or calcium diphosphate. Example 1 reports a solid mass containing 60 g of polyethylene glycol 6,000, 15 g of polyvinyl chloride and 25 g of activated dinethicone (sirketone) which can be ground and filled with solid gelatine capsules or can be filled with form tablets. 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 various oils; a liquid silicone, such as duneticone or sirneticone; a glycerol polymer, such as polyethylene glycol 600, 800 or 1,200; and a glycol, such as ethyl glycol, propylene glycol or glycerol. - r "Simethicone has been incorporated in oral formulations < Syrup or liquids with a clear base. O. Banga and co-authors, in Incorporation of Simethicone into Syrup or Clear Base L Guid Oráis, Drug Development and Industrial Pharmacy, 15 (5), pages 691-704 (1989), describe a variety of vehicles for ló. simethicone, but reports that the best results were obtained with neutralized CORBOPOLCR) resins (full carboxypolirnet) in combination with glycepna and propylene glycol. U.S. Patent Nos. 4,772,472 and 4,894,978 to Schonmann and co-inventors refer to gelatin capsules having at least two identical active ingredients in two different carrier substances, or at least two different active ingredients in two identical carrier substances. The carrier substances are provided in the capsule in a layer ratio, side by side, without a dividing or separating wall. There is a need for a gelatin capsule containing multiple phases or regions of semi-solid filling materials, containing a therapeutically effective amount of a pharmaceutical product. At least one of the regions or phases must be substantially translucent in order to provide a different visual appearance. The serrulled filling materials must be sufficiently viscous to prevent them from being easily expelled from the cover of the syringe capsule, in order to minimize the potential for product violation.

SUMMARY OF THE INVENTION The present invention provides a dosage form having a common shell, of a polymeric material. The envelope contains first and second phases which are arranged in discrete regions of the envelope and which are in mutual contact at least at one interface. Each of the first and second phases contains a sernisolide filler material, and at least one phase contains an active ingredient. The first and second phases differ in composition and at least one of the phases has a hardness of less than 1,300 UTN (nefe lornet rich turbidity unit). In another embodiment of the present invention, the common shell of polyimepco material is a soft gelatin capsule containing a first phase that is substantially translucent and a second phase that is opaque, resulting in a dosage form that It has a different appearance. In yet another embodiment of the present invention, the serums forming the first and second phases are sufficiently viscous so that they can not be expelled at room temperature from the dosage form with a syringe, which preferably has a gauge needle. 16 or less *.

DETAILED DESCRIPTION OF THE PREFERRED MODALITIES The present invention relates to a pharmaceutical dosage form containing a common shell of polyrneric material. The envelope may be in the form of a soft gelatin capsule or a hard gelatin capsule of two. pieces. The envelope of polyinepic material contains multiple phases, which are differentiable on a qualitative and / or quantitative basis. As used in the present invention, it is intended that phase will mean a sernisolide filler material that may contain an active ingredient. i5 The phases in the envelope can be arranged in a variety of designs or sequences. In general, the phases are in a layer arrangement side by side, where they are in mutual contact at least at one interface. Alternatively, the phases can be arranged randomly within of the envelope, in an arrangement that is not layered or veined. The composition of each phase depends on the use to which the dosage form is intended. The phase can virtually contain any active ingredient, such as pharmaceutical products, '? 5 vitamins and minerals. The active ingredient or active ingredients are present in the phases in therapeutically effective amounts, which are amounts that produce the desired therapeutic response when administered orally, and can be readily determined by one skilled in the art. In determining these amounts, the particular compound being administered, the bioavailability characteristics of the compound, the dose regimen, the age and weight of the patient, and other factors should be considered. Since the phases are in the form of an ernisolone gone, two adjacent phases may contain active ingredients that are incompatible with each other, since there is minimal diffusion between the layers. The phases may also contain active ingredients that are coated or otherwise processed to provide a delayed or sustained release. For example, an analgesic can be formulated in an easy release form in a first phase, while the same analgesic with a delayed release coating is used in the second phase. When administering it, this dosage form provides a sustained or prolonged release profile. In addition to coatings that affect the rate of dissolution, enteric or other coatings may be employed to control where the active ingredient is released into the body. For aesthetic reasons, it may be convenient to formulate one or more of the phases so that it is free of any active ingredient. This placebo phase can then be formulated to give the desired visual appearance, such as translucent, opaque or colored. As used in the present description, a sernisolide is a system of at least two constituents that consist of a condensed loop that encloses, and is interpenetrated by, a liquid. The semi-solid filler material is sufficiently viscous for 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 gauge needle 16 or less. It is also possible to roll the visual appearance of the phases, depending on the formulation used to form the semi-solid filling material. The dosage form can contain either an opaque or a translucent phase, or two translucent phases. If two translucent phases are used, dyes can be added to form regions that have different colors. In a preferred form of the present invention, the multiphase dosage form has both opaque and translucent phases. In yet another preferred embodiment of the present invention, the dosage form contains a first opaque phase containing anti-latent? N, such as simethicone or dimethicone, and a substantially translucent second phase containing an antidiarrheal, such as an overnight lobar hydrochloride. . Since the active ingredients are arranged in different phases, the detrimental effect of the ethicone on a dissolution profile of the loperated hydrochloride ida is avoided. Specifically, this problem is solved without the use of a barrier layer, such as that set forth in European Patent Publication No. 0 571 217, assigned to the same caterer as the present invention, published on November 24, 93. The following illustrates the translucent and opaque phases that can be employed in the present invention.

THE TRANSLUCENT PHASE The solid translucent serine of the present invention contains a liquid polyalkylene glycol having an average molecular weight of about 600 or less. The polyalkylene glycol serves as a solvent for the pharmaceutical product. A suitable polyalkylene glycol is polyethylene glycol. The polyethylene glycols preferably have an approximate molecular weight of 200 to 600 and, better still, about 300 to 400. The translucent sepusolide generally comprises, by weight, about 35 to 99, preferably 85 to 99 percent, solvent. Unless stated otherwise, the percentages mentioned herein are by weight with respect to the total weight of the semi-solid, translucent filler material, ie, both the sernisolide and the active ingredient. The translucent serylene is formed by thickening the solvent with cellulose ethers. A suitable cellulose ether is hydroxypropyl cellulose. Preferably the thickening agent is hydroxy roxycellulose NF, which has an approximate molecular weight of 80,000 to 1,150,000. Hydroxypropylcellulose NF can be obtained commercially from Aqualon, Tnc. under the KLUCEL brand < R), and the preferred grades are KLUCEL GF, MF and HF, which have a molecular weight scale of about 370,000 to 1,150,000. Low molecular weight hydroxypropylcellulose, which includes KLUCEL EF, LF and JF, may also be used, which have a scale of about 80,000 to 140,000, but in general, at higher concentrations than the higher molecular weight grades. In a preferred embodiment the thickening agent is employed in an amount effective to form an isolide which is substantially translucent and sufficiently viscous, so that it can not be expelled at room temperature with a syringe having a 16 gauge needle. or less. In general, the sernisolide contains, by weight, from 0.10 to 10, preferably from 0.25 to 3.5 percent, approximately, of one or more of the cellulose ethers. In addition to the polyalkylene glycol, the semi-solid may contain solubilizing agents to increase the solubility or dispersibility of the active ingredient in the senisolide. Suitable agents include propylene glycol, glycerin, ethanol, N-methyl-2-pyrrolidone, dimethylisosorbide, povidone (PVP), poloxamer, other pharmaceutically active agents and mixtures thereof. A preferred poloxamer (the copolymer of poly (oxetane) -poly (oxypropylene)) is Poloxamer 124, obtainable from BASF under the trademark PLURONIC L 44. Generally, the semifold comprises from about 0 to about 8 preferably from 0 to 6%, of solubilizing agent. In addition, the sernisolide may contain from 0 to 10%, approximately, of ag? A. If acetic acid, fataid, radicide, cirnetidine or other readily oxidizable substance is used as active ingredient, it may be advisable to include * an anti-oxidant to eliminate degradation or discoloration, such as acetamofen. The active ingredient or pharmaceutical active ingredients are (are) present in the dosage form in a therapeutically effective amount. Pharmaceutical products suitable for use in the invention include: acetaninophen, famotidine, chlorphemranine, pseudoephedrine, dex t rornetorfan, di fenhi drainma, bro eni amma, clernastine, phenylpropanolamine, terfenadine, astenizole, loratadine, overnight, N-oxide of lorernide, ranitidine, cytidine, t ama dol, cisapride, acetiisalicylic acid, doxilarnma succinate, pharmaceutically acceptable salts and mixtures thereof. In general, the pharmaceutical product comprises about 0.1 to 40, preferably 0.2 to 30% by weight of the total solids composition. Various other pharmaceutically acceptable excipients may be included in the senisolide filler material, such as preservatives, for example, rnetii- or propylparaben; coloring agents, sabot ant agents, lubricants, flow improvers, an oxidants, surfactants, plasticizers, filler auxiliaries and other compounds, agents and components, which will produce an attractive final product. The semi-solid translucent filler material generally has a turbidity of less than about 1,300, preferably less than about 200 UTN. In a preferred embodiment a filling for a soft gelatin capsule containing about 180 rng / rnl of inofen acetates, comprises, by weight, about 10 to 40% of acetaminophen, about 40 to 90% of polyethylene glycol, which has an average molecular weight of 400 (PEG 400); from 0 to about 8% by weight, from 0 to about 8% of propylene glycol and from about 2 to 8% of the hydroxy propyl 1-cellate. In another preferred embodiment, a filling for a soft gelatin capsule containing from 10 to 40 rng / ml of farnotidm, comprises, by weight, about 0.5 to 4% of farnotidm, of 60 to 99% by weight of PEG 400; from 0 to around * of 8% water; from 0 to about 8% propylene glycol and from 2 to 8% hydroxypropylcellulose. In a further preferred embodiment, a filling for a soft gelatin capsule containing 17 mg / rnl of loperated hydrochloride comprises, by weight, about 1 to 3% of ida loperahydrochloride, from 92 to 99% of PEG 400; from 0 to about 8% water, from 0 to 8% propylene glycol and from 0.5 to 3% hydr-o prilcelulose.

Lfl FOSE OPOCO The opaque selenium of the present invention also contains polyalkylene glycol. The polyalkylene glycols include: polyethylene glycol (PEG) having an average molecular weight of from 400 to 20,000, suitably, preferably from 400 to 3,350. The opaque semi-solid generally comprises, by weight, from 30 to 70, preferably from 40 to 60 percent of the polyalkylene glycol. Unless stated otherwise, the percentages mentioned herein are by weight, with respect to the total weight of the opaque sernisolide filler material, that is, both the sernisolide and the antiflute. Mixtures of PEGs of various molecular weights can also be used in the opaque semisolid filler material of the present invention. The mixtures will generally contain PEG of low molecular weight, which have an average molecular weight of about 600 or less, mixed with PEG of high molecular weight, which have a molecular weight pro dium of RNA of 600 to about 10,000, in amounts that produce an isolide. Preferably said mixtures contain about 0.25 to 5% PEG of low molecular weight and about 45 to 50% of high molecular weight PEG. In addition to the liquid polyalkylene glycol, the opaque semi-solid may contain one or more auxiliary, sernisolide-forming agents, in the amount shown (percent by weight of senilsolide):% Component e 0.05-10 propylene glycol 0.05-15 Stearic Pl? Rol (6-dieste (0.05-10 Polyethylene glycol oleate) 0.05-5 Hydroxypropyl cellulose NF (KLUCEL HF, molecular weight 1, 150,000) Opaque sernisolide can contain from 0 to about 10% water. The slow antiflat is present in the opaque phase of the dosage form in a therapeutically effective amount. Antiflatulents suitable for use in the invention include ethicone and dimethicone. In general, the antifattulent comprises from 30 to 70, preferably from 40 to 60 weight percent, approximately, of the total filler material soldered. The dehusking time of the semi-solid filling material containing the anti-sufiantile preferably is less than 15, preferably less than 9 seconds. Various other pharmaceutically acceptable excipients, such as preservatives, for example, rnethyl- or propylparaben, coloring agents, flavoring agents, lubricants, flow improvers, anti-oxidants, humectants (glycerin), agents, may be included in the opaque semisolid filler material. surfactants, plasticizers, fillers and other compounds, agents and components that produce an attractive final product. In a preferred embodiment, the solid solder filling that contains 547 mg / rnl of simethicone comprises, by weight, about 40 to 60 percent ethicone, about 1 to 3 percent liquid polyethylene 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 sernisolide preferably has an approximate viscosity of 900,000 to 1,000,000 cp at 25 ° C, a deferring time of less than about 8 seconds (when measured by the USP method described below) and a possibility of syringe handling less than 0.5 g (when measured by the method described below). The filler material of the present invention can be used in commercially available soft gelatin capsules, such as those that can be obtained commercially from R. P: Scherer or from 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 a semi-solid is formed, the resulting dosage form has an opaque white appearance; or dyes can be added to obtain any desired color. When a translucent filler material is introduced into the capsule and forms a semisolid, the corresponding region of the dosage form has an elegant, translucent or clear appearance. You can also color or dye the translucent filler with coloring agents. The filling materials are heated before being loaded into the capsule, because they are extremely viscous at temperatures below 40 ° C. Soft filled gelatine capsules can be filled by hand with a syringe. The filling of hot liquid is loaded into a syringe. The needle of 1 A syringe is used to puncture one end of the soft gelatin capsule so that the appropriate amount of filling material can be injected by hand. This procedure is repeated for each sernisolide filler material, so that the resulting dosage form has discrete layers or phases in a side-by-side relationship. Alternatively, the two or more semisolid, different filling materials can be randomly introduced to produce a random design of solid phases. The capsule is to be cooled with the filling materials.

The r-ellene material can also be introduced into the soft gelatin capsule using the equipment and encapsulation techniques known in the art, such as those described in US Patents 4,772,472 and 4,894,978 Shonn ann and co-inventors, which are incorporated here as a reference As previously described with the hand filling technique, the filling should be maintained at more than about 40 ° C during the filling operation, so that it flows easily into the capsule. Accordingly, the filler can be stored in a jacketed container and can be transported through a thermostatically controlled feed tube to the encapsulation equipment. Specific embodiments of the present invention are illustrated, by way of the following examples. This invention is not confined to the specific limitations set forth in these examples, but rather well within the scope of the appended claims. Unless stated otherwise, the percentages and proportions given below are by weight with respect to the total composition. The viscosity was measured in the following examples using a Rheometrics 8400 fluid spectrometer at 25 ° C. Using a parallel plate of 25 rn and a constant tension of 10%, frequency sweeps were performed. The viscosity was recorded at a frequency of 1.0 radian per second.

The defoaming test was carried out in the following examples using the specifications and procedures of the United States Pharmacopoeia 23 rev., The National Formulary, 18a. edition. The foaming solution consisted of 1% octoxmal-9 and 0.0005% FDSC Blue # 1 in ag? A. The test equipment comprised a weight-action shaker with a radius set at 13.3 ± 0.4 c (measured from the center of the arrow to the center of the bottle). An equivalent of 20 g of sirketone was transferred to a jar containing 100 ml of sputtering solution, previously heated at 37 ° C. The jar was covered and shaken at a 10 ° arc at a frequency of 300 ± 30 strokes / minute, for 10 seconds. The time it took for a portion 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 syringe said formulation within a controlled period of time. This test was used as a measure of the resistance to violation. We used 10 cc syringes with 16 gauge needles, 3.81 cm long. The syringe was placed in the formulation, pulled up on the plunger and held for 10 seconds. The weight of the material brought to the syringe was recorded. The turbidity of the filler materials described in the following examples was measured using a Hach Ratio / XR Turbidimeter turbidity meter. The United States Pharmacopoeia defines turbidity as the light diffusing effect of suspended particles, and turbidity as the measure of the decrease in intensity of the incident ray per unit length of a given suspension. This instrument measures turbidity within a scale of 0.00 to 2,000 NTU. As a reference point, the turbidity of the water is zero. Samples of the approximately 8 ml fill materials were transferred to 13 x 100 mm Fisher Brand culture tubes immediately after manufacture. The samples of filling material were stored at room temperature, since they were prepared several days in advance. The outer surface of each of the sample culture tubes was treated with silicone oil just before measuring the turbidity. The turbidity of the samples was determined at room temperature. The turbidity of two sample tubes of each filling material was measured and the average of the results is reported. The dissolution test was carried out in the following examples using USP type I baskets, fixed at 100 rpm, and an acetate buffer (pH 4.7) with pepsin as medium. The volume was 500 mi, the USP limits are 80% of TMN in 30 minutes. An amount of the formulation equivalent at a dose of 4.0 mg of ida loperahydrochloride was tested in a soft gelati capsule, cut in half. 92 EXAMPLE 1 This example provides a comparison of PEG mixtures similar to those described in the publication of TCP UO 91/07950. The following mixtures were prepared: Quantity (% w / w) Component Sample A Sample B PEG 600 64.40 64.40 PEG 1450 26.20 26.20 PEG 3500 - 4.20 PEG 8000 4.20 Glycerol 5.20 5.20 Samples were prepared as follows:) PEG and glycerol were weighed. 2) The mixture was placed on a previously heated hot plate, fixed to the highest setting. It was mixed with heat (approximately 75 ° C) until a clear solution was obtained. 3) The mixture was removed from the heat and mixed. It was sonically treated with a temperature setting of 69 ° C. Upon enrichment at room temperature to form a gel, both samples had an opaque white appearance, with a turbidity of more than 2,000 NTU.

EXAMPLE 2 This example describes a translucent sernisolide filler material of the present invention containing about 180 mg / rnl of acetaminoren. The filling contains: Component Quantity (% weight /? That) Acetarninof n 20.0 PEG-400 (molecular weight 400) (5. 7 Hi droxipropilcel? Slab 4.3 (KLUCEL GF, molecular weight 300,000).

The sample is prepared as follows: 1) PEG-400 is heated to 110-120 ° C and the acetamofen is slowly added while stirring. 2) After acetannofen is in solution, hydroxypropylceiulose is added with stirring. 3) After the appearance of the resulting mixture is that of a clear solution, it is allowed to cool to room temperature.

EXAMPLE 3 This example describes a translucent serisolide filler material of the present invention containing 10 mg / ml of fa otidine. The filling material contained: Component Quantity (% weight / weight) Farnotidma 1.6 PEG 400 (Molecular weight 400) 91.3 Hydroxypropylcellulose 7.1 (KLUCEL GF, molecular weight 300,000) The sample was prepared as follows: 1) The PEG-400 was heated at 110-120 ° C and the hydroxypropylcellulose was slowly added while stirring. 2) After the hydroxypropyl cellulose remained in solution, the formulation was cooled to approximately 70 ° C. 3) The phantom was added while stirring. 4) After the resulting mixture had a clear solution appearance, it was cooled to room temperature to give a Laro semi-solid. The turbidity of the resulting sample was 14.6 UTN.

EXAMPLE 4 This example describes a sernisolide filler material of the present invention which contains 17 mg / ml loperamide hydrochloride. The filling materials contained: Quantity (% weight / weight) A Hydroxypropylcellulose (KLUCEL HF, molecular weight 1,150,000) 0.5 0.5 Propylene glycol - 6.0 PEG 400 98.0 92.0 Loperamide hydrochloride 1.5 1.5 Samples were prepared as follows: 1) PEG 400, propylene glycol and hydroxypropylcellulose were weighed in a beaker. 2) Mix at high speed on hot plate, regulated at approximately 120 ° C until the polymer completely dissolves. 3) The heat is reduced to approximately 70 ° C and the loperamide hydrochloride is added, mixing until it dissolves. The resulting formulations are allowed to cool to room temperature to give a clear semisolid.

EXAMPLE 5 This example describes translucent senisolide fillers containing 17 mg / l of loperated hydrochloride. The filling materials contained: Component Quantity (% weight / weight) A B Hi roxypropyl cellulose (KLUCEL NF, molecular weight 850,000) 3.0 3.0 Propylene glycol ~ - 6.0 PEG 400 95.5 89.5 LOPERNID HYDROCHLORIDE 1.5 1.5 The samples were prepared as follows: 1) PEG 400, propylene glycol and hydroxypropyl 1-cellulose, were weighed into a beaker. 2) It was mixed at high speed on a hot plate, regulated at around 120 ° C, until the polymer was completely dissolved. 3) The heat was reduced to approximately 70 ° C and the loperatide hydrochloride was added; It was mixed until it dissolved. The resulting formulations are cooled or cooled to a rinsed sernisolide.

EXAMPLE 6 This example describes a translucent sernisolide filler material containing 17 mg / l of loperartuda hydrochloride. The filling material contained: Component Quantity (% weight / weight) Hydroxy ropilcel? Slab (KLUCEL HF, molecular weight 1,150,000) 1.5 Propylene glycol 5.5 PEG 400 91.5 Chloride of lopera ida 1.5 The sample was prepared as follows: 1) PEG 400, propylene glycol and hydroxypropylcellulose are weighed in a beaker. 2) Mix at high speed on a hot plate, regulated at approximately 1 0 ° C, until the polymer is completely dissolved. 3) The heat is reduced to approximately 70 ° C and the loperamide hydrochloride is added, mixing until it dissolves. The resulting formulation is allowed to cool to room temperature to give a clear semisolid.

EXAMPLE 7 This example describes a reagent material that is translucent solved that contains 17 rng / rnl of working temperature.

Component Quantity (%? That /? That) Hydroxypropylcellulose (KLUCEL MF, molecular weight 850,000) 2.7 Propylene glycol 5.5 PEG 400 90.3 Loperamide hydrochloride 1.5 The sample was prepared as follows: 1) PEG 4000, propylene glycol and hydroxypropylcell ulose were weighed in a beaker. 2) Mix at high speed, on hot plate, regulated approxinadarnent at 120 ° W, until the polymer completely dissolved. J) The heat was reduced -about 70 ° C and the ida loperahydrochloride was added, mixed until dissolved. The resulting formulation was allowed to cool to room temperature to give a clear semisolid. The following summarizes the results of the sample test for examples I and 3-7.

Handling with clarity Viscosity Example syringe (g) (UTN) (cPs) lA > 2,000 IB > 2,000 3 14.6 4 0.06 69.810 5A 0.08 34 18.200 5B 0.06 21 87.870 6 0.32 5.5 78.070 0.23 10.2 156.900 Robitussi (R > Liq? I-GelsCR) 1.6 Dpxorai < R) Cough Liqui -6els < R > 3.2 Water 11.5 EXAMPLE 8 This example describes opaque sernisolide fillers of the present invention containing 547 rng / ml of syn- ticone. The following samples were prepared: Quantity (% by weight / weight) Component A B C D E PEG 1450 50.0 PEG 3350 50.0 PEG 4600 50.0 PEG 8000 50.0 PEG 20,000 50.0 SIMETICONE (Dow Corning) 50.0 50.0 50.0 50.0 50.0 Samples were prepared: 1) PEG was weighed. 2) The PEG was melted and stirred on a hot plate, regulated at about 80 ° C, until it was clear. 3) Simethicone was slowly added 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 sernisolides.

EXAMPLE 9 This example describes opaque semi-solid r-ellene materials of the present invention containing 547 mg / rnl of sirneti cona. The following samples were prepared: Quantity (% w / w) Component A B C D PEG 400 0.5 0.5 0.5 0.5 PEG 1450 49.5 PEG 3350 49.5 -G 4600 49.5 PEG 8000 49.5 Imaginary (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, adjusted at approximately 80 ° C, until they were clear. 3) Simethicone was slowly added and stirred at high speed for about 20 minutes. 4) It is removed from the heat and allowed to cool without agitation. The resulting samples were opaque sernisolides.

EXAMPLE 10 This example describes r-elleno sernisolide materials of the present invention containing 547 ng / ml of sirnet icone. The following samples were prepared: (Quantity (% by weight / weight) Component B C ü ._ PEG 400 3.0 3.0 3.0 3.0 PEG 1450 47.0 PEG 3350 - 47.0 PEG 4600 - - 47.0 PEG 8000 - - - 47.0 Yes metícona (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 isolides.

EXAMPLE 11 This example describes an opaque semi-solid filler material of the present invention, which contains 547 ng / ml of sirketone. The next sample was prepared.

Component Quantity (% weight / weight) PEG 400 2.5 PEG 3350 47.5 birneticone (Dow Corning) 50.0 The samples were prepared using the procedure of Example 2. The resulting sample was an opaque solid semí. The following summarizes the results of the sample tests of examples 8 to 11 and the control of sirneticone: Handling with de-Viscosity Time Example syringe (g) foaming (sec) (cPs) 8A 0.047 11 3,009,000 8B 0.091 5 1,420,566 8C 0.180 9 331,700 8D 0.216 5 213,420 8E 0.300 8 9.069 gfi - 9B 0.054 6 2,856,000 gc 9D Handling with de-Viscosity Time Example syringe (g) foaming (sec) (cPs) 10A --- -10B 0.039 10 301,000 10C 1ÜD 0.165 7 116.350 U 0.347 6 1,025,633 Simeticona 1.675 9 612 (Dow Corning) In the case where multiple tests were carried out with the same formulation, the above data are an average of the values measured for the formulations. The semi-solids of the present invention have defoaming times equal to or faster than the ethicone control. In addition, the syringe handling of the isolides of the present invention was significantly lower than the simethicone control and the defoaming times were less than, or substantially equivalent to, those of the ethicone control.

EXAMPLE 12 This example describes a soft gelatin capsule filled with a semi-solid, translucent filler material containing 17 rng / ml of loperamide hydrochloride and an opaque isolide filler containing 547 g / ml of simethicone.

Preparation of the translucent phase Component Canity (% Weight / weight) Hydroxypropylcellulose (KLUCFL MF, molecular weight 850,000) 2.7 Propylene glycol 5.5 PEG 400 90.3 Harvested hydrochloride 1.5 The sample was prepared as follows: 1) The PEG 400 is weighed , propylene glycol and hydroxypropyl cellulose to a beaker. 2) Mix at high speed on hot plate, regulated at around 120 ° C, until the polymer is completely dissolved. 3) Heat is reduced to around 70 ° C and loperamide hydrochloride is added, mixing until dissolved. The resulting formulation was allowed to cool to room temperature to give a clear semisolid having a + i? rb? dez approximately 7.0 UTN, a dissolution of around ')% of lopera hydrochloride gone in 30 minutes, and a possibility of handling with syringe of around 0.40 g.

Preparation of the opaque phase Component Quantity (% weight / weight) PEG 400 2.5 PEG 3350 47.5 Si et icone (Dow Corning) 50.0 The sample was prepared as follows: 1) PEG 2 is weighed) It is melted and stirred on hot plate, regulated at about 80 ° C. 3) Simethicone is added slowly and stirred at high speed. 4) Remove from heat and let cool. The resulting formulation was an opaque isolide having a defoaming time of about 6 seconds and a viscosity of 3,000,000 cP.

Preparing the soft-phase two-phase gelatin capsule (translucent / opaque) The semi-solid filling materials were heated so that each of them would flow and then filled with hydrophobic and hydrophilic soft gelatin capsules, as follows: 1) The cylinder of a 10 cc syringe was filled with the opaque formulation of simethicone, without the needle. 2) A 16-gauge needle was connected and placed in a soft, filled gelatin filled with air, previously weighed. 3) I carefully pass a dose of 125 rng sirnet icona, inside the capsule full of air, with a syringe. 4) The cylinder of a second 10 cc syringe was filled with the loperamide hydrochloride formulation, without the needle. 5) A 16 gauge needle was connected and placed inside the soft gelatin capsule, filled with simethicone. 6) A dose of 2 rng loperamide hydrochloride was carefully passed over the simethicone layer with the syringe. 1) The upper part of the capsule is sealed with a hot iron 5. The resulting soft gelatine capsules had an opaque, distinct white layer (of simethicone) in a side-by-side relationship with a substantially translucent layer (of ida loperahydrochloride). EXAMPLE 13 This example reports the results of the dissolution and defoaming tests carried out on the formulations of Examples 7 and 11, in a side-by-side arrangement, and two control formulations. In all tests the sernisolides were introduced into the test case without a gelatin capsule shell. To simulate the multi-phase dose form of the present invention, the semi-solids of Examples 7 and 11 were introduced into the test apparatus in a side-by-side arrangement. The two semi-solids were in contact with each other at least in one interface, but the two formulations did not mix with each other. The sernisolide of example 7 was present in an amount that provided 2 mg of loperamide hydrochloride, while the semisolid of example 11 was present in an amount that produced 125 mg of sirketone. Farnbien was also prepared two control samples. Control A was prepared by mixing an amount of example 7 which produced 2 mg of loperamide hydrochloride, with an amount of example 11 which gave 125 g of ethicone. Then the two sernisolides are mixed intimately and se > introduced the resulting mixture into the test apparatus. The mixture that was introduced into the apparatus was substantially homogeneous and did not exhibit phases or layers other than solids. Control B was prepared by mixing an amount of the sernisolide from Example 7 which gave 2 mg of ioperamide hydrochloride with 125 mg of simethicone oil. The resulting mixture was then introduced into the test apparatus. The results of the purification and dissolution tests are reported below: % of dissolution of the sample time HCl of loperarnida.- desspumación 15 rnin. 30 rnm. Control A 59 85 16 sec Control B 3 3 > 1 rnm Example 13 75 91 7 sec As shown by the above data, the use of the solvents of the present invention, in a side-by-side arrangement, provided a significantly increased lug solution compared to an intimate mixture of the two formulations (control fl) or the formulation in which the oil was mixed with the ida loperahydrochloride isolide (control B). The data also shows that the dessp-rinnation time of the sernisolides of the present invention, in a side-by-side arrangement, was significantly better than the controls. This example demonstrates that the formulations of the present invention in a side-by-side arrangement substantially eliminates the deleterious effects that simethicone oil has on the solution of the loperated hydrochloride. Various modifications can be made to the modalities described above, without departing from the spirit and scope of the present invention.

Claims (9)

NOVELTY OF THE INVENTION CLAIMS

1. - A pharmaceutical dosage form, characterized in that it comprises: a common envelope of polymeric material; a first phase comprising a first semisoli or filling material; a second phase comprising a second solid filling material; and at least one of said first and second phases contains an active ingredient; each of the first and second phases is arranged in discrete regions of the envelope and in mutual contact in at least one inter-phase; the first and second phases differing in their composition and at least one of said phases has a turbidity of less than 1,300 UTN. ? . - The dosage form according to claim 1, further characterized in that each of the first and second phases contains an active ingredient. 3. The dosage form according to claim 1, further characterized in that the first phase is substantially opaque and the second phase is substantially translucent and has a turbidity of less than 1,300 UTN. 4. The dosage form according to claim 1, further characterized in that the first and second active ingredients are the same. 5. The dosage form according to claim 1, further characterized in that the first and second active ingredients are different. 6. - The dosage form according to claim 1, further characterized in that the first and second phases are arranged on the cover in a side-by-side arrangement. 7. The dosage form according to claim 1, further characterized in that the first and second phases are arranged leatoriamente in the cover 8. The dosage form according to claim 1, further characterized in that the envelope is a cover of gelatin capsule. 9. The dosage form according to claim 7, further characterized in that the shell is a soft gelatin capsule shell. 10. The dosage form according to claim 1, further charac- terized because the active ingredient is a pharmaceutical product. 11. A pharmaceutical dosage form, characterized in that it comprises: a gelatin capsule shell; a first phase comprising a first isolide containing a polyalkylene glycol having an average molecular weight of about 600 or less and a cellulose ether in an amount effective to thicken the polyalkylene glycol; a therapeutically effective amount of a first pharmaceutical ingredient dissolved or suspended in the first semi-solid; and the first is solid has a turbidity of less than about 1,300 UTN; a second phase comprising a second solid filler containing a polyalkylene glycol having an average molecular weight of about 400 to 20,000, and a therapeutically effective amount of a second pharmaceutical ingredient disposed therein; and each of the first and second phases is arranged in discrete regions of the cover and in contact with each other at least in one interim. 1

2. The dosage form according to claim 11, characterized in that in the first semi-solid the polyalkylene glycol is polyethylene glycol. 1

3. The dose form according to claim 11, further characterized in that the turbidity of the sernisolide prirner is less than about 200 UTN. 1

4. The dosage form according to claim 11, further characterized in that the first semi-solid comprises additional propylene glycol. 1

5. The dosage form according to claim 11, further characterized in that the first semi-solid comprises, by weight: about 35 to 99 percent of the polyalkylene glycol, about 0 to about 10 percent of propylene glycol; from 0 to about 10 percent water; and about 0.1 to 10 percent, of cellulose ether. 1

6. - The dosage form according to claim 15, further characterized in that the first isolide comprises polyethylene glycol having an average molecular weight of 200 to 600, approximately. 1

7. The dosage form according to claim 11, further characterized in that in the first sernolide the cellulose ter is hydroxypropylcellulose. 1

8. The dosage form according to claim 17, further characterized in that in the pprner the cellulose ether is isolido is hydroxypropylcellulose having a molecular weight of about 80,000 to 1,150,000. 1

9. The dosage form according to claim 11, further characterized in that the first pharmaceutical ingredient is selected from the group consisting of acetarni ofén, famotidine, chlorphenirane, pseudoephedrine, dext rornethorphan, diphenylhydramine, brornpheniramine, clernastine, "enilpropanola , terfenadine, asternizole, loratadine, loperazone, N-oxide of lopera ida, ramtidine, cirnetidine, tramadol, cisappde, acetylisalicylic acid, doxylamine succinate, pharmaceutically acceptable salts and mixtures thereof. with claim 12, further characterized in that the first semi-solid comprises polyethylene glycol having an average molecular weight of about 300 to 400, and hydroxypropylcellulose 21. The composition according to claim 20, further characterized in that the first sernisolide comprises, by weight: about 85 to 99 percent, of polyethylene glycol having a mole weight average- from 300 to 400, approximately; from 0 to about 8 percent, propylene glycol; and about 0.25 to 3.5 percent, of a hydroxypropylcellulose having an average molecular weight of about 300,000 to 1,200,000. 22. The dosage form according to claim 21, further characterized in that the first semi-solid has a viscosity of at least 30,000 centipoise at 25 ° C. 23. The composition according to the embodiment 22, further characterized in that the first solid semidry comprises, by weight: from about 1 percent, of loperamide hydrochloride; about 92 to 99 percent, of polyethylene glycol having an average molecular weight of about 400; from 0 to about 8 percent of water, from 0 to about 8 percent of propylene glycol; and from 0.5 to 3 percent, approximately, of hydrox i pr-o ?? lcel ulosa. 24. The dosage form according to claim 11, further characterized in that in the second sernisolide the polyalkylene glycol is polyethylene glycol. 25. The dosage form according to claim 11, further characterized in that the second solder sol has an approximate viscosity of 10,000 to 2,500,000 centipoises at 25 ° C. 26. The dosage form according to claim 11, further characterized in that the second semi-solid additionally comprises auxiliary agents or forms, selected from the group consisting of propylene glycol, 1,6-d-stearate, polyglycerol, and the like. , glycerol oleate and hydroxypropyl 1 ulose cell. 27. The dosage form according to claim 11, further characterized in that the second semi-solid comprises, by weight: about 30 to 70 percent, of polyethylene glycol; and about 30 to 70 percent, of an anti-flatulent. 28. The dosage form according to claim 11, further characterized in that the second semi-solid comprises, by weight, 0.25 to 5 weight percent of a polyethylene glycol having an average molecular weight of 600 or less and about 45 weight percent. to 50 percent of a polyethylene glycol having an average molecular weight of more than 600 to 10,000, approximately. 29. The dosage form according to claim 11, further characterized in that the second sernisolide comprises a flatulent anti- and has a defoaming time of less than about 15 seconds. 30. The dosage form according to claim 11, further characterized in that the second sernisolide has a syringe handling possibility of less than 0.5 grams. 31. The dosage form according to claim 11, further characterized in that in the second sernisolide the pharmaceutical product is selected from the group consisting of sirketone and dimet i cona. 32. The dosage form according to claim 11, further characterized in that the second sernisolide comprises, by weight: about 40 to 60 percent of letile glycol having an average molecular weight of 400 to 3.350, apr-ox nail; and about 40 to 60 percent, if ethicone. 33.- The dose form in accordance with the rr-? V nication 32, also characterized because the second solid serní has a viscosity of 400,000 to 2,000,000, approximately, of centipoises, at 25 ° C. 34.- The dosage form according to claim 11, further characterized in that the second semi-solid comprises, by weight: about 40 to 60 percent, of simethicone; about 1 to 3 percent, of ileoglycan poly ict having an average molecular weight of about 300 to 400; and about 40 to 60 percent, of polyethylene glycol having an average molecular weight of about 1,450 to 4,600. 35. The dosage form according to claim 34, further characterized in that the second semi-solid has a viscosity of about 900,000 to 1,000,000 centipoise at 25 ° C; a defoaming time of less than about- 8 seconds and a syringability of less than about 0.5 g.