Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Cosmetic – antiperspirant – dentifrice
Reexamination Certificate
2000-01-18
2001-11-06
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Cosmetic, antiperspirant, dentifrice
C424S456000, C424S451000, C424S464000, C424S443000
Reexamination Certificate
active
06312704
ABSTRACT:
TECHNICAL FIELD
The invention relates to a composition which can be administered, in particular, orally, for pharmaceutical or cosmetic use, capable of forming a microemulsion in situ with the biological fluid of the body. The invention relates more especially to a composition composed of a self-microemulsifying carrier system for pharmaceutical active ingredients (also referred to herein as “agents”), designated in the art by the English term “SMEDDS” (self-microemulsifying drug delivery system). These systems have the property of microemulsifying in water at the temperature of the human body.
This composition is intended on the one hand to transport one or more soluble or sparingly soluble pharmaceutical active ingredients and on the other hand to form a microemulsion with the biological fluid of the human body, being understood that one or more pharmaceutical active ingredients or principles in solution in a microemulsion has better bioavailability.
PRIOR ART
As is known, a microemulsion is a fluid and stable homogeneous solution composed of four major constituents, respectively, a hydrophilic phase, a lipophilic phase, at least one surfactant (SA) and at least one cosurfactant (CoSA).
Microemulsions have been widely studied for oil recovery. There is hence no need to describe them here in detail.
A surfactant is a chemical compound possessing two groups, the first polar or ionic, which has a great affinity for water, the second which contains a longer or shorter aliphatic chain and is hydrophobic. These chemical compounds having marked hydrophilic character are intended to cause the formation of micelles in aqueous or oily solution.
A cosurfactant, also sometimes known as “co-surface-active agent”, is also a chemical compound, but having hydrophobic character, intended to cause the mutual solubilization of the aqueous and oily phases in a microemulsion.
The invention is hence directed to increasing the bioavailability of pharmaceutical active ingredients which are difficult to dissolve, by solubilizing them within a microemulsion.
In the document EP-A-0,334,777, the Applicant has shown the possibility of using microemulsions in the pharmaceutical industry. In the document WO 93/12766, the Applicant has described particular compositions for pharmaceutical use, in the form of microemulsions intended to be packaged in the form of suppositories, in which the hydrophilic phase is supplied by the rectal fluid. This production gives excellent results for suppositories, but cannot meet the needs for compositions intended to be ingested orally, since the amount of biological fluid in the stomach or intestine is much larger than in the rectum (several deciliters). Now, the conditions of existence of microemulsions such as those described in the document WO 93/12766 necessitate a very small percentage of water (few milliliters).
In the document EP-A-0,152,294, a system of the type in question has been described, consisting of a lipophilic phase composed of oleic alcohol and/or of polar esters of C
2
-C
4
alcohols with C
8
-C
12
fatty acids, and, as surfactant, ethoxylated glycerol, the mixture containing from 35 to 85% by weight of water. These formulations contain appreciable proportions of water, thereby ruling out the form of presentation in hard gelatin capsules. On the other hand, the compositions containing water form a macroemulsion in situ and not a microemulsion, thereby greatly decreasing the bioavailability.
In the document WO 93/23083, published after the priority date of the present application, a system is described in which the anhydrous hydrophilic phase consists of a polyglycolized glyceride containing C
8
-C
10
short chains. This system does not significantly improve the diffusion of pharmaceutical active agents through membranes. It does not enable hydrophilic pharmaceutical active agents to be transported, and does not permit the formation of an emulsion, still less of a microemulsion in situ, thereby not facilitating bioavailability.
The pharmaceutical and cosmetic industries are expressing an ever increasing demand for compositions free from an aqueous phase, in order to facilitate their packaging in the form of hard gelatin capsules, tablets and plasters. The compositions known at the present time for the manufacture of hard gelatin capsules, in particular the ones described In the above documents, are unable to meet the need, since the presence of water contained in these mixtures is incompatible with the technique employing hard gelatin capsules.
The invention solves these problems. It relates to an orally administrable composition, in particular for pharmaceutical or cosmetic use, comprising a lipophilic phase, at least one surfactant and at least one cosurfactant which, mixed and in the presence of physiological fluid, form a microemulsion facilitating dissolution in situ and improving the bioavailability of the pharmaceutical active ingredients.
DESCRIPTION OF THE INVENTION
This orally administrable composition capable of forming a microemulsion, comprising at least
a pharmaceutical active ingredient,
a lipophilic phase consisting of a mixture of fatty acid esters and glycerides,
surfactant(SA),
a cosurfactant (CoSA),
and is characterized
in that the lipophilic phase consists of a mixture of C
8
to C
18
polyglycolized glycerides having a hydrophilic-lipophilic balance (HLB) of less than 16, this lipophilic phase representing from 1 to 75% of the total weight of the composition;
the surfactant (SA) is chosen from the group comprising saturated C
8
-C
10
polyglycolized glycerides and oleic esters of polyglycerol, this surfactant also having an HLB of less than 16;
the cosurfactant (CoSA) has a different composition from the surfactant and consists of ethyl diglycol or a polyvalent alcohol selected from the group comprising lauric esters of propylene glycol, oleic esters of polyglycerol; and
the SA/CoSA ratio is between 0.5 and 6.
The hydrophilic phase used to form the final microemulsion is supplied after ingestion by the physiological fluid of the digestive milieu.
In other words, the invention consists in having selected a particular lipophilic phase which, combined with specific surfactants and cosurfactants, forms a microemulsion in the presence of the physiological fluid of the stomach and intestine of the human or animal body. This composition improves the bioavailability of the pharmaceutical active ingredients within the body. The composition according to the invention can thus be administered effectively via the oral route.
Surprisingly, the use of lipophilic phase having considerable chain length enables the diffusion through membranes and the passage of pharmaceutical active ingredients or agents into the blood to be significantly improved.
In the description and in the claims:
“C
8
-C
18
polyglycolized glycerides” denotes the lipophilic phase which is a reaction product consisting of a mixture of mono-, di- and triglycerides and polyethylene glycol (PEG) mono- and diesters, preferably of molecular weight between 200 and 4,000 and free glycerol and free PEG. The HLB value of the polyglycolized glycerides is adjusted by the length of the PEG chain and the melting point is adjusted by the length of the chains of the fatty acids, of the PEG and by the degree of saturation of the fatty chains. The HLB of the lipophilic phase is less than 16. The reactions employed to make the reaction product include partial alcoholysis of a starting oil consisting of a mixture of mono-, di- and triglycerides of fatty acids with PEG or esterification of glycerol and PEG with fatty acids or by mixing of glycerol esters and condensates of ethylene oxide with fatty acids, said fatty acids being selected from the group consisting of caprylic, capric, lauric, myristic, palmistic, stearic, oleic, linoleic and linolenic acids, at least 60% by weight in respect of total fatty acids containing 12 or more carbon atoms.
“C
8
-C
10
polyglycolized glycerides” denotes the surfactant which is a reaction product consisting of a mixture of mono-, di- and triglycerides and pol
Denis Joel
Farah Nabil
Gattefosse S.A.
Norris & McLaughlin & Marcus
Page Thurman K.
Shelkh Humera N.
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