Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
2001-07-20
2004-04-13
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S452000, C424S456000, C424S462000
Reexamination Certificate
active
06720002
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to the field of pharmaceutical compositions. In particular, the invention pertains to pharmaceutical formulations containing antihistamines, such as, loratadine and its derivatives that are formulated for use in conjunction with soft gelatin capsules.
BACKGROUND OF THE INVENTION
Two identified histamine receptors are the receptors H-1 and H-2. The H-1 receptors mediate the response antagonized by conventional antihistamines. H-1 receptors are present in the mammalian skin, ileum and bronchial smooth muscle.
Non-narcotic or non-sedating hydrophobic antihistamine compounds such as loratadine and its derivatives are known. Loratadine was first described in U.S. Pat. No. 4,282,233 to Vilani. Loratadine is an H-1 histamine receptor protein antagonist which binds to peripheral H-1 receptors as discussed in Quercia et al.,
Hosp. Formul.,
28, p.137-53 (1993). Loratadine is useful as an antihistamine and has little or no sedative effects. Thus, loratadine provides an antihistamine effect while still allowing the user to perform mental or physical functions requiring high levels of concentration. A variety of other therapeutic treatments using loratadine alone or in combination with other active ingredients have been suggested, such as treatment of seasonal or perennial rhinitis, allergic asthma, and motion sickness. See Aberg et al., U.S. Pat. No. 5,731,319, for example. Antiarrhythmic uses, such as treatment of atrial fibrillation (AF), have also been suggested, as described in Buckland et al., U.S. Pat. No. 6,110,927.
Loratadine derivatives which share antihistamine properties of loratadine have also been developed. Active metabolites such as decarbalkoxylated forms of loratadine have been of interest. One such metabolite derivative is 8-chloro-6,11-dihydro-11-(4-piperidylidine)-5H-benzo-[5,6]-cyclohepta-[1,2-b] pyridine, also known as descarboethoxyloratadine (DCL) which is described in U.S. Pat. No. 4,659,716. U.S. Pat. No. 5,595,997 to Aberg et al discloses methods of utilizing DCL for the treatment of allergic rhinitis and other disorders without adverse side effects.
Other patents relating to loratadine or a chemically related antihistamine, including any pharmaceutically acceptable salt thereof, in various dosage forms include U.S. Pat. No. 5,100,675 to Cho et al.; U.S. Pat. No. 4,990,535 to Cho et al.; and U.S. Pat. No. 5,314,697 to Kwan et al.
Oral dosage forms, such as loratadine-containing tablets and syrups, are known and marketed under the names Claritin®, Claratin Reditabs® and Claratin-D® 24-Hour etc. (commercially available from Schering-Plough Corporation, N.J.).
These commercial products are described in U.S. Pat. No. 4,282,233 to Villani; U.S. Pat. No. 4,659,716 to Villani; U.S. Pat. No. 4,863,931 to Schumacher et al.; U.S. Pat. No. 6,132,758 to Munayyer et al. U.S. Pat. No. 6,132,758 discloses an antihistaminic syrup stabilized against degradation of the active ingredient by the addition of about 0.05 to 5 mg/mL of an amino-polycorboxylic acid. This patent teaches that under certain storage conditions losses of active agent can occur.
U.S. Pat. No. 4,910,205 to Kogan et al discloses a transdermally acceptable composition comprising an effective amount of loratadine or its decarbalhoxylation product, about 40-70% weight % of a volatile solvent, about 5-50% by weight of a fatty acid ester and about 2-60% of an essential oil.
While syrup, solid and fast dissolving dosage forms are available for loratadine type antihistamines, there presently exists a need for a soft capsule dosage form. The soft capsule dosage form has many advantages known to those skilled in the art, however, formulating hydrophobic drugs into solutions for encapsulation into a soft capsule can present many problems. Oral delivery systems for hydrophobic drugs are known. Lacy et al. U.S. Pat. No. 6,096,338 describes delivery systems for hydrophobic drugs including histamine H-1 receptor antagonists such as loratadine. The carrier systems disclosed include a digestible oil, preferably mixtures of partial or complete esters of medium chain fatty acids, and a pharmaceutically acceptable surfactant component comprising a hydrophilic surfactant containing a transesterification product of polyoxyethylene glycol with glycerol esters of capric and/or caprylic acids. This surfactant disperses the oil in vivo without substantially inhibiting in vivo lipolysis of the oil. The reference does not, however, specifically address the problems associated with storage stability and recrystallization of loratadine and its derivatives in soft capsule dosage forms.
Hydrophobic solvents are preferred for use in soft capsules so as to reduce the hydrophilic nature of the fill, wherein migration of water through the soft capsular material into the fill composition can cause recrystallization and precipitation of the active ingredient under storage conditions. One problem associated with hydrophobic solvents, however, is that they are known to adversely affect bioavailability of the drug. Compounds such as loratadine are susceptible to recrystallization and therefore experience the solvent system challenges associated with soft capsules. Ideally, a solvent system for loratadine and its derivatives is one which is hydrophobic, protonic and water-dispersible.
There thus exists a need for improved pharmaceutical formulations containing loratadine and derivatives thereof for use in soft capsules which solubilize loratadine and exhibit long-term storage stability at ambient conditions without recrystallization. There is also a need for a solvent system which does not adversely affect bioavailability of the active ingredient. Even more desirable would be a formulation which satisfies both of these criteria and also increase the fill concentration of loratadine. This would permit the use of smaller size capsules for a given dose of active.
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™ 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™ 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™ MCM C-8;
c) povidone; and
d) Polysorbate™ 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 dig
Lin Jing
Truong Hung
Nickey Donald O.
Page Thurman K.
R.P. Scherer Technologies, Inc.
Rozycki Andrew G.
Young Micah-Paul
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