Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
2001-12-21
2003-11-25
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S451000, C424S452000, C424S456000, C514S970000, C514S785000, C514S786000
Reexamination Certificate
active
06652880
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to pharmaceutical compositions for oral administration. In particular, the invention relates to liquid pharmaceutical compositions suitable for softgel encapsulation.
BACKGROUND OF THE INVENTION
A number of drugs are known to require formulation in the presence of fatty acids, such as oleic acid, to provide optimum conditions for bioavailability. For example, long-chain fatty acids can be predisposed for lymphatic absorption, and therefore, are useful in pharmaceutical formulations in which the lymphatic system is the desired target site for the active ingredient. One of the problems associated with the formulations containing fatty acids is that chemical instability can arise due to their acidic nature and the presence of reactive carboxyl groups. Esterification can occur with drug molecules containing alcohol groups or transesterification of ester molecules.
In the past, this problem has been solved by continuing to use free fatty acids in formulations which are encapsulated in softgel capsules and storing the capsules under refrigerated conditions to reduce the rate of reaction between the drug and fatty acids. However, where the drug is not sufficiently soluble in the formulation, cold storage methods result in crystallization which in turn necessitates equilibrating the capsules at room temperature to ensure crystal dissolution prior to consumption. Accordingly, complex storage regimens are required throughout the supply chain for the use of such formulations.
Lacy et al. in Patent Cooperation Treaty WO 95/24893 published Sep. 21, 1995 discloses a carrier system for a hydrophobic drug which comprises a digestible oil and a pharmaceutically acceptable surfactant for dispersing the oil in vivo upon administration of the carrier system, the surfactant comprising a hydrophilic surfactant component which does not substantially inhibit the lipolysis of the digestible oil, and a lipophilic surfactant component which substantially reduces the inhibitory effect of the hydrophilic surfactant. Suitable digestible oils are complete or partial esters of medium chain (C
8
-C
12
) or long-chain (C
14
-C
22
) fatty acids with low molecular weight (up to C
6
) mono-, di- or polyhydric alcohols. Medium chain length triglycerides or long chain tri- and diglyceride mixtures which may contain monoglycerides are particularly preferred. Fractionated coconut oil is a preferred oil.
The lipophilic surfactants used include fatty acids; mono- and/or diglycerides of fatty acids; acetic, succinic, lactic, citric and/or tartaric esters of mono and/or diglycerides of fatty acids; propylene glycol mono- and/or di-esters of fatty acids; polyglycerol esters of fatty acids; castor oil ethoxylates; acid and ester ethoxylates; and sorbitan esters of fatty acids.
The hydrophilic surfactants used have a hydrophilic/lipophilic balance (HLB) value greater than 10 and include phospholipid; polyoxyethylene sorbitan fatty acid derivatives; castor oil or hydrogenated castor oil ethoxylates; fatty acid ethoxylates; alcohol ethoxylates; polyoxyethylene, polyoxypropylene co-polymers and block co-polymers; anionic surfactants and alkylphenol surfactants.
The formulations may contain ethanol as a co-solvent and formulations containing up to 15% by weight ethanol are disclosed.
Perry et al. in Patent Cooperation Treat WO 97/40823 published Nov. 6, 1997 discloses a pharmaceutical composition comprising a hydrophobic drug; a digestible oil selected from triglycerides or propylene glycol esters of medium chain length (C
8
-C
12
) and/or long chain length (C
13
-C
22
) fatty acids; propylene glycol monolaurate (lauroglycol), a lipophilic surfactant which comprises a glyceride of a C
5
to C
10
fatty acid; and a hydrophilic surfactant which is a polyoxyethylene hydrogenated castor oil, wherein the digestible oil is present in an amount in the range from 3.0 to 12.0% by weight of the composition and the weight ratio of hydrophilic surfactant to lipophilic surfactant is in the range of 1:1.5 to 1:2.5. The formulations may contain ethanol as a co-solvent for the drug and formulations containing 15-25% by weight ethanol are disclosed.
There still exists the need for pharmaceutical compositions having improved stability which promote systemic absorption.
SUMMARY OF THE INVENTION
The invention discloses a liquid pharmaceutical composition wherein the active ingredient is dissolved in a liquid vehicle comprising a combination of long chain glycerides and lipophilic surfactant. The composition according to the invention are stable and promote systemic absorption and can be used for oral formulations containing drugs or active ingredients susceptible to the adverse affects of carboxyl groups in carrier ingredients. The invention is particularly useful for oral formulations containing testosterone undecanoate (also referred to as TU).
According to the invention there is provided a liquid pharmaceutical composition comprising a drug dissolved in a liquid vehicle, the liquid vehicle comprising:
a) a glyceride of a long chain fatty acid having a chain containing from 14 to 22 carbon atoms and is present in an amount from about 15% to about 70% by weight, preferably from about 15% to about 60% by weight of said liquid vehicle;
b) a lipophilic surfactant having an HLB of less than 10 and present in an amount of from about 30% to about 60% by weight of said liquid vehicle.
The composition according to the invention contains a liquid vehicle which is substantially devoid of free fatty acids and contains less than 10% by weight ethanol.
The composition can further comprise a hydrophilic surfactant, which can be present in an amount of from about 0% to about 35% by weight of the liquid vehicle.
In one embodiment of the invention, there is provided a liquid pharmaceutical composition for oral administration having testosterone undecanoate dissolved in a liquid vehicle, the liquid vehicle consisting essentially of:
a) a glyceride of a long chain fatty acid having a chain containing from 14 to 22 carbon atoms; and
b) lauroglycol.
It has now been found that the stability problem associated with free fatty acids can be avoided by the use of glycerides in which the fatty acids are esterified with glycerol to form a neutral compound which is less reactive. Thus, the invention minimizes or excludes the use of free fatty acids in the compositions.
Suitable glycerides for use in the invention are mono-, di- and triglycerides. Preferred glycerides are triglycerides, as they contain the highest fatty acid content. Long chain glycerides can liberate long chain fatty acids following lipolysis in the gastrointestinal tract. The long chain triglycerides are desirable to promote lymphatic absorption in a manner similar to the respective fatty acids. See, for example, Henk de Nijs,
Acta Technol
., 33(4) pp.163-168 (1987), which discusses the enhancement of lymphatic absorption by using triglycerides and different absorption mechanisms involved with long and medium chain fatty acids.
In the present invention, the presence of the lipophilic surfactant, and optionally the additional hydrophilic surfactant, enhances the solubility of drugs in the liquid triglyceride carrier while maintaining the stability of the composition.
The invention is particularly useful in pharmaceutical compositions containing drugs, i.e., active ingredients, compounds, pro-drugs and the like, which encounter stability problems when combined with free fatty acids. Preferred compositions of the invention are those containing testosterone undecanoate (TU).
DETAILED DESCRIPTION OF THE INVENTION
As used herein and in the claims, the terms “drug” and “active ingredient” are used synonymously to refer to pharmaceutical compounds or molecular structures. When used within the context of the invention, the terms refer to pharmaceutical compounds which can be used in association with the liquid carrier of the invention to produce the resulting pharmaceutical composition.
The phrase “substantially free from free fatty acid” as used within the context of d
Aylwin Elizabeth Anne
Banbury Susan
de Nijs Henrik
Ferdinando Josephine Joan Christine
Nickey Dobald O.
R.P. Scherer Technologies, Inc.
Rozycki Andrew G.
Spear James M.
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