Title:  Antihistamine formulations for soft capsule dosage forms

United States Patent:  6,720,002

Issued:  April 13, 2004

Inventors:  Lin; Jing (Mulgrave, AU); Truong; Hung (Chadstone, AU)

Assignee: R.P. Scherer Technologies, Inc. (Paradise Valley, NV)

Appl. No.: 909313

Filed: July 20, 2001

Abstract

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 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) Polysorbate.TM. 80 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) CAPMUL.TM. MCM C-8;

c) povidone; and

d) Polysorbate.TM. 80.

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) Polysorbate.TM. 80; 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[5,6]cyclohepta[1,2-b]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, decarboalkoxylated forms of loratadine, such as 8-chloro-6,11-dihydro-11-(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 are mixtures of caprylate and caprate. 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 Polysorbate.TM. 80 (a polyoxyethylene sorbitan fatty acid esters). Mixtures of povidone and Polysorbate.TM. 80 can preferably be present in a weight ratio of about 10:1 to about 15:1, respectively.

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, polyglycolysed 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. 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 and Polysorbate.TM. 80 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. Those skilled in the art will appreciate what 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 dosage forms, such as soft gelatin capsules, containing the loratadine compositions of the invention can be orally administered to patients in need of Hi receptor antagonist or antihistamine treatment.

The invention can be further illustrated by the following Examples:

EXAMPLE 1

Process of Preparing Loratadine Formulation

CAPMUL.TM. MCM C8, povidone, and Polysorbate.TM. 80 were combined. The mixture was heated to about 60^oC. until the povidone was completely dissolved. Loratadine was added to the mixture and the resulting mixture was stirred until the loratadine was completely dissolved. The mixture was cooled to room temperature. The formulations prepared are summarized in Table 1 below:

EXAMPLE 2

Preparation of Comparative Loratadine Formulations

In a manner similar to that of Example 1, the following formulations were prepared in accordance with the corresponding ingredients and proportions:

EXAMPLE 3

Comparative Storage Stability Study of Loratadine Compositions

The storage stability test was conducted on each of the above formulations by subjecting samples of each formulation to varying conditions. Each sample was prepared by either filling 3DXHB gel pouches with the formulation or a screw-capped brown glass bottle. Some of the samples were tested using pouches that were unsealed, and some of the samples tested were sealed using fresh gel. Each pouch sample was subjected to the following conditions: 1) 22^oC. under ambient humidity, 2) 30^oC. under 75% relative humidity (corresponding to accelerated solution stability test conditions), and 3) 5^oC. under ambient humidity.

As can be seen from the data in the above Table, no observable crystallization occurred in the conventional Macrogol.TM. 400 formulation in the capped vials at 5^oC. and ambient humidity conditions. On the other hand, the Macrogol.TM. 400 formulation crystallized when stored in the open gel bag. The results demonstrate that exposure of loratadine formulations to ambient moisture causes crystallization over time.

As can be seen in the above Table, none of the formulations tested had observable crystallization during a storage period of 80 days when contained in the capped vial at 22^oC. and ambient humidity conditions.

As can be seen from the above data, storage at 30^oC. and 75% relative humidity resulted in observable crystallization of the conventional loratadine formulations in the Macrogol.TM. 400 solvent system, and crystallization occurred in both sealed and open gel bag containment. In the case of Formulas 1--1 and 1-2, crystallization occurred more rapidly in the open gel bag than the sealed gel bag.

As the data shows, storage conditions of 30^oC. and 75% relative humidity of loratadine formulations with a solvent system of Macrogol.TM. 400 in combination with povidone did not prevent crystallization from occurring in either sealed or open gel bags.

The above data shows that loratadine formulations in a Macrogol.TM. 400 solvent system and Polysorbate.TM. 80 did not prevent crystallization under 30^oC. and 75% relative humidity storage conditions.

As can be seen from the above data, loratadine formulations prepared in accordance with Formula 4-1 of the invention as described above exhibited no observable crystallization even after 71 days in storage at 30^oC. with 75% relative humidity conditions in either the open or sealed gel bag containment. Further yet, no observable crystals were present in Formulation 4-1 of the invention even after 16 months in the sealed gel pouch containment.

INDUSTRIAL APPLICABILITY

The loratadine compositions of the invention provide for the use of loratadine in soft capsule dosage forms such as soft gelatin capsules by improving its solubility under storage conditions without adversely affecting its bioavailability. The compositions of the invention offer the additional benefit of increasing the concentration of solubilized loratadine per total fill volume, which permits smaller fill volumes to be used to deliver the same dosage of the drug. Accordingly, smaller capsule sizes can be used to administer the drug to patients, thereby increasing patient comfort and reducing manufacturing costs.

The complete disclosures of all patents, patent applications and publications are incorporated herein by reference as if each were individually incorporated by reference. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications can be made while remaining within the spirit and scope of the invention.

Claim 1 of 20 Claims

What is claimed is:

1. A pharmaceutical composition for use in soft capsule dosage forms comprising:

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

b) a solvent system comprising a mixture of medium chain fatty acids;

wherein said loratadine and derivatives thereof is present in an amount of about 6.3% by weight of the total composition.

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