The invention herein relates to a pharmaceutical composition containing loratadine and derivatives thereof which is suitable for use in soft capsule dosage forms. A pharmaceutical composition according to the invention comprises loratadine and derivatives thereof in a pharmaceutically effective amount; and a solvent system comprising a mixture of medium chain fatty acids. The loratadine compositions exhibit good solubility and storage stability while maintaining bioavailability of the drug. The compositions also permit high concentrations of solubilized loratadine per total fill volume and thereby permit the use of smaller capsules to deliver the same dosage of drug.

SUMMARY OF THE INVENTION

The invention provides for a pharmaceutical composition comprising loratadine and its derivatives together with a solvent system for use in soft capsules. Loratadine compositions of the invention exhibit unexpected and improved solubilization properties at ambient storage conditions over extended period of time without recrystallization and precipitation of loratadine. The inventive composition also permits higher concentrations of loratadine to be delivered within a given fill volume. As a result, the total amount of fill volume needed to administer the same dosage of loratadine is reduced, and smaller capsule sizes can be used thereby improving patient comfort and reducing manufacturing costs.

The invention provides a pharmaceutical composition for use in soft capsules comprising loratadine and derivatives thereof and a solvent system comprising a mixture of mono- and diglycerides of medium chain fatty acids. In a more preferred embodiment the invention provides a pharmaceutical composition that additionally comprises a dispersant. In a most preferred embodiment the dispersant comprises povidone and polyoxyethylene sorbitan fatty acid ester (e.g., Polysorbate.TM. 80).

There is further disclosed a pharmaceutical composition for use in soft capsule dosage form consisting essentially of:

a) loratadine and derivatives thereof present in an amount of about 6.3% by weight of the total composition;

b) mono- and di-glycerides of medium chain fatty acids present in an amount of about 87% by weight of the total composition;

c) povidone present in an amount of about 6.3% by weight of the total composition; and

d) polyoxyethylene sorbitan fatty acid ester present in an amount of about 0.8% by weight of the total composition.

There is also disclosed a pharmaceutical composition for use in soft capsule dosage forms consisting essentially of:

a) decarbalkoxylated loratadine derivative in a pharmaceutically effective amount;

b) mono- and di-glycerides of medium chain fatty acids comprising caprylic acid and capric acid;

c) povidone; and

d) polyoxyethylene sorbitan fatty acid ester.

There is further disclosed a soft capsule dosage form comprising a fill composition consisting essentially of:

a) loratadine and derivatives thereof in a pharmaceutically effective amount;

b) a mixture of mono- and diglycerides of medium chain fatty acids;

c) povidone;

d) polyoxyethylene sorbitan fatty acid ester; and wherein said soft capsule has a capsule size of 5 minim or less.

Loratadine is the drug name given to the compound known as ethyl 4-(8-chloro-5,6-dihydro-11H-benzo.left brkt-top.5,6.right brkt-bot.cyclohepta.left brkt-top.1,2-b.right brkt-bot.pyridin-11-ylidene)-1-piperidinecarboxylate.

Loratadine derivatives include compounds having the structural formula of loratadine and having substituents differing from that of loratadine and having substantially the same chemical and therapeutic properties. Loratadine derivatives include, but are not limited to, decarboalkokylated forms of loratadine, such as 8-chloro-6,11-dihydro-1-(4-piperidylidine)-5H-benzo-[5,6]-cyclohepta-[1,2- -b] pyridine, also known as descarboethoxyloratadine (DCL); and azatadine. As used herein and in the claims the phrase "loratadine and derivatives thereof" means loratadine or any chemically related antihistamine, including any pharmaceutically acceptable salt thereof. Chemically reacted antihistamines include any halogenated H-benzo-cyclohepta-pyridine.

Loratadine and derivatives thereof can be present in an amount of about 6.3% or less by weight of the total fill composition. Typically, loratadine and derivatives thereof can be present in an amount of about 6.3% to about 3.0% by weight of the total fill composition.

Solvent systems which can be used in accordance with the invention are those which are both moderately lipophilic and have hydrogen bonding capability. Preferably, the solvent system has a hydrophilic lipophilic balance (HLB) value ranging from about 3 to about 7, more preferably ranging from about 4 to about 5. The preferred solvent system of the invention contains a mixture of mono- and diglycerides of medium chain fatty acids. Preferred mixtures of mono- and diglycerides of medium chain fatty acids comprise mixtures of caprylic and capric acid. Most preferred as the mixture of mono- and diglyceride medium chain fatty acids is CAPMUL.TM. MCM-C8 (available from Abitec Corporation, Northampton, England). The mono- and diglyceride mixture can be present in an amount of about 89.0% by weight or less of the total fill composition. When CAPMUL.TM. MCM-C8 is used, it is preferably present in an amount ranging from about 89.0% to about 70.0%, more preferably about 89.0% to about 80%, by weight of the total fill composition.

The solvent system can further comprise a dispersant composition to enhance uniform dispersibility of the fill in water or gastric juices. The amount of the additional dispersant, however, is present in amount sufficient to enhance uniform dispersion of the fill in water or gastric juices without significantly increasing the volume of the fill. When a dispersant is used, it is preferred that the dispersant be present in an amount of 8.0% by weight of the fill or less. More preferred is a dispersant present in an amount of from about 7.5% to about 5.0%, most preferably from about 7.5% to about 7.0%, by weight of the total fill composition.

A preferred dispersant is a mixture of povidone (polyvinylpyrrolidone) and polyoxyethylene sorbitan fatty acid ester. Suitable polyoxyethylene sorbitan fatty acid esters which can be used include, but are not limited to, Polysorbate.TM. 80. Mixtures of povidone and Polysorbate.TM. 80 can preferably be present in a weight ratio of about 10:1 to about 15:1, respectively. Other polyoxyethylene sorbitan fatty acid esters which can be used include Polysorbate.TM. 40, Polysorbate.TM. 60, Polysorbate.TM. 20 and Polysorbate.TM. 120.

Compositions according to the invention do not require the presence of additional ingredients such as additives and stabilizers typically associated with soft capsule fill formulations. Without these additional ingredients higher concentrations of loratadine and derivatives thereof can be obtained within smaller fill volumes as compared to existing formulations.

The invention further provides a soft dosage form having a pharmaceutical composition comprising loratadine and derivatives thereof and a solvent system having a mixture of medium chain mono- and diglycerides. In one embodiment, the invention includes a soft capsule comprising a storage stable composition having 10 mg of loratadine in solubilized state in a capsule size as small as 3 minims.

DETAILED DESCRIPTION OF THE INVENTION

The loratadine compounds of the invention can be prepared according to the method described in Villani U.S. Pat. No. 4,282,233, the entire text of which is incorporated herein by reference. The starting materials and reagents to prepare loratadine and its derivatives are well known in the art and readily available, and loratadine and its derivatives can be synthesized using conventional organic synthesis techniques. Metabolic derivatives of loratadine, such as decarbalkoxylated forms of loratadine, can be prepared by removal of the carbethoxy moiety according to methods known in the art and as described in U.S. Pat. No. 4,659,716, the entire text of which is incorporated herein by reference. For example, loratadine can be refluxed in the presence of sodium hydroxide and ethanol to remove the carbethoxy moiety from the piperidine ring of the compound structure.

Solvent systems which can be used in accordance with the invention are those which are both moderately lipophilic and have hydrogen bonding capability. Preferably, the solvent system has a hydrophilic lipophilic balance (HLB) value ranging from about 3 to about 7, more preferably ranging from about 4 to about 5. Suitable solvent systems include, but are not limited to, polyglycolized glycerides (such as LABRAFIL.RTM. WL 2609BS available from Gattefosse, Binfield, U.K.), propylene glycol monolaurate (such as LAUROGLYCOL.TM. 90 available from Gattefosse), propylene glycol monocaprylate (such as CAPRYOL.TM. 90 available from Gattefosse), and mono- and diglyceride medium chain fatty acids. Most preferred is the mono-, diglyceride medium chain fatty acid mixture CAPMUL.TM. MCM C8 (commercially available from Abitec Corporation).

The solvent system can further comprise a dispersant composition to enhance uniform dispersibility of the fill in water. The amount of the additional dispersant, however, is present in amount sufficient to enhance uniform dispersion of the fill in water or gastric juices without significantly increasing the volume of the fill. When a dispersant is used, it is preferred that the dispersant be present in an amount of 8.0% by weight of the fill or less. Most preferred is a dispersant present in an amount of from about 7.5% to about 7.0% by weight of the total fill composition.

The dispersant composition used in accordance with the invention can be a combination of povidone together with a surfactant. Suitable surfactants which can be used include, but are not limited to, non-ionic surfactants having an HLB value ranging from about 14 to about 17; polyoxyethylene sorbitan fatty acid esters, such as Polysorbate.TM. 40, Polysorbate.TM. 80, Polysorbate.TM. 60, Polysorbate.TM. 20, and Polysorbate.TM. 120; ethoxylated aliphatic alcohols, such as Oleth-20 (Volpo.TM. 20 available from Croda, Inc., Parsippany, N.J.), Ceteareth-20 (Volpo.TM. CS-20 available from Croda, Parsippany, N.J.); and caprylocaproyl macrogol-8 glycerides (LAUROGLYCOL.TM. 90 available from Gattefosse).

A preferred dispersant is a mixture of povidone and Polysorbate.TM. 80. Mixtures of povidone (polyvinyl pyrrolidone) and Polysorbate.TM. 80 (polyoxyethylene sorbitan fatty acid monooleate) can be present in a ratio of about 10:1 to about 15:1.0, respectively.

Soft capsules containing pharmaceutical compositions can be prepared using conventional and known encapsulation techniques, such as that described in Stroud et al., U.S. Pat. No. 5,735,105, the entire text of which is incorporated herein by reference. In general, the formulation is deposited between two opposing ribbons of a gel composition. The composition of the ribbons may include gelatin, modified starches, gums, carrageenans and mixtures thereof.

Carrageenans are water-soluble gums comprising linear polysaccharides with a sugar backbone of alternating units consisting of galactose units linked by 1,3-.beta.-D-linkages, as well as 1,4-.alpha.-D-linkages. The fundamental properties of iota, kappa and lambda are a function of the number and position of the ester sulfate groups. Preferred carrageenan capsule materials are those comprising iota-carrageenan. Iota-carrageenan contains approximately 30% by weight 3,6 anhydro-D-galactose and 32% ester sulfate by weight. Particularly preferred are iota-carrageenan materials described in Tanner et al., U.S. Pat. No. 6,340,473, the entire text of which is incorporated herein by reference, which comprises iota-carrageenan, modified starch, plasticizer and a dibasic buffer system. Carrageenan-containing capsule materials are available under the tradename VEGICAPS.TM. and available from Cardinal Health, Inc., Somerset, N.J.).

Modified starches that can be used in accordance with the invention include hydroxypropylated starches, acid thinned starches and the like. The only native starch determined to be functional with iota-carrageenan in preparing the capsular material films of the invention is potato starch, and the term "modified starch" is meant to include native, unmodified potato starch. In general, modified starches are products prepared by chemical treatment of starches, for example, acid treatment starches, enzyme treatment starches, oxidized starches, cross-bonding starches, and other starch derivatives. It is preferred that the modified starches be derivatized wherein side chains are modified with hydrophilic or hydrophobic groups to thereby form more complicated structure with a strong interaction between side chains.

Suitable plasticizers include the materials used for the same purpose in the manufacture of mammalian gelatin capsules. Representative plasticizers are any of a variety of polyhydric alcohols such as glycerin, sorbitol, propylene glycol, polyethylene glycol and the like. Other plasticizers can include saccharides and polysaccharides, which can be prepared by hydrolysis and/or hydrogenation of simple or complex polysaccharides.

Other components can also be incorporated into the carrageenan capsule compositions provided they do not alter the melting point/fusion point characteristics of the film. Representative of these additional components, typically added during the molten state of the capsule composition, include flavoring agents, opacifying agents, preservatives, embrittlement inhibiting agents, colorants, dyes and pigments, and disintegrants. Use of conventional pharmaceutical or food grade ingredients are acceptable.

Those skilled in the art will appreciate what capsule material compositions are suitable. The opposing ribbons are then run between two die rollers having die pockets thereon the surface of which corresponds to the configuration of the desired soft capsule. The composition is sealed within the fused casing.

When formulated in accordance with the invention, a 10 mg loratadine dose can be accommodated by a 5 minim or less size oval soft capsule. A 10 mg loratadine dose can be contained within a capsule size as small as a 3 minim size oval soft capsule. Capsule size volumes of the invention are herein expressed in terms of minims. A minim is a pharmaceutical volumetric unit of measure wherein 1 minim=0.0616 cc.

Soft capsule forms, such as soft gelatin or Vegicaps.TM. soft capsules, containing the loratadine compositions of the invention can be orally administered to patients in need of H1 receptor antagonist or antihistamine treatment.

 

Claim 1 of 7 Claims

1. A soft capsule dosage form comprising a fill composition consisting essentially of: a) a decarbalkoxylated loratadine derivative in a pharmaceutically effective amount; b) a mixture of mono- and diglycerides of medium chain fatty acids; c) povidone; d) polyoxyethylene sorbitan fatty acid ester; and wherein said soft capsule has a capsule size of 5 minim or less to about 1 minim; and wherein the soft capsule comprises a capsule material comprising carrageenan.
 

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