Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form
Reexamination Certificate
1997-05-14
2001-02-27
Mullis, Jeffrey C. (Department: 1711)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
C424S439000, C424S484000, C424S486000, C514S772000
Reexamination Certificate
active
06193985
ABSTRACT:
The present invention is directed to new pharmaceutical compositions for delivery of biologically active agents. More particularly, the invention concerns the use of a tocopherol or a derivative thereof to prepare compositions having low irritability suitable for administration to mucosal membranes and which may be used efficiently to administer drugs, which are substantially insoluble or only sparingly soluble in water.
For systemic action, drugs are normally administered by mouth and are then absorbed in the gastrointestinal tract. However, this mode of administration is not suitable in all circumstances, for example in the case of drugs which are metabolised to any significant degree by the liver or which are poorly absorbed. In other cases, the oral route may be impractical, for example in patients suffering from nausea or who are unconscious. Before surgery, oral administration is not advisable because of the risk of vomiting and in many cases, a more rapid effect may be required than can be achieved by the oral route.
In these circumstances the parenteral route is frequently used, most notably intravenous or intramuscular injection. However, whilst this provides a convenient way of achieving a strong and rapid systemic effect, it has a number of disadvantages including the requirement for sterile equipment and trained personnel. It is also unpleasant to the patient.
Moreover, in cases where a systemic effect is not required, local administration may be preferable, for example to avoid side effects, to reduce the dosage, or simply to facilitate the administration.
Such problems have lead in recent years to an increasing interest in developing formulations for the topical administration of drugs, and in particular for topical administration involving absorption from mucous membranes.
Topical administration has the advantage that drugs may be administered readily and simply to achieve a systemic or dermal, regional or localised effect, as required. However, topical absorption of drugs through the skin can be slow, and in many cases transmucosal routes of delivery are preferred. Since it may be performed by untrained personnel and permits therapeutic plasma levels of drugs rapidly to be achieved, intranasal administration has received particular attention in this regard.
For topical delivery, biologically active drugs are normally administered in the form of aqueous solutions. However, many biologically active compounds are substantially insoluble or only sparingly soluble in water and in such cases, organic solvents are required to dissolve these agents. The problem here is that mucosal tissues are generally very sensitive and such solvents are frequently too irritant to be of clinical use. Thus for example, Lau and Slattery [Int. J. Pharm. 1989, p. 171-74] attempted to administer the benzodiazepines diazepam and lorazepam by dissolving these compounds in a range of solvents including: triacetin, DMSO, PEG 400, Cremophor EL, Lipal-9-LA, isopropyladipate and azone dodecyle-aza-cycloheptane-2-one. Whilst many of the solvents dissolved diazepam and lorazepam in the desired concentrations, when administered to the nose they were too irritant to be of use. Thus, Cremophor EL was found to be the least irritative for mucosal tissue, but nasal absorption using this solvent is rather slow and peak concentration is low relative to that found after iv. administration.
Triglycerides such as vegetable oils are generally non-irritant, but usually these oils are too poor as solvents to be of any use.
Attempts have been made to develop various other vehicles for transmucosal delivery of drugs, such as benzodiazepines, having limited water solubility. Thus, for example WO 86/04233 of Riker discloses a pharmaceutical composition wherein the drug (eg. diazepam) is dissolved in a mixture of propellant and co-solvent eg. glycerolphosphatide. The composition requires a pressurized system and at least one halogenated hydrocarbon aerosol propellant.
In U.S. Pat. No. 4,863,720 of Burghardt, a sublingual sprayable pharmaceutical preparation is disclosed, in which the active drug can be a benzodiazepine, optionally comprising polyethylene glycol (PEG) and requiring ethanol, di- and/or triglyceride of fatty acids and a pharmaceutically acceptable propellant gas.
U.S. Pat. No. 4,950,664 of Rugby-Darby describes the nasal administration of benzodiazepines in a pharmaceutically acceptable nasal carrier. The carrier may be a saline solution, an alcohol, a glycol, a glycol ether or mixtures thereof.
In PCT WO 91/16929 of Novo Nordisk, glycofurols or ethylene glycols are suggested as carriers for a variety of drugs, including benzodiazepines, which may be used on mucous membranes.
Another solution proposed to this problem, has been the use of micelles or liposomes, but these are frequently difficult to produce on a technical scale.
A further constraint concerning nasal administration is that a small administration volume is required; it is not generally possible to administer more than about 0.1 ml per dose per nostril. Therefore, a great need exists for solvents, in which, on the one hand the solubility of the active drug is high, and which, on the other hand, are non-irritating to the mucosa.
The aim of the present invention is to provide a solution to the above mentioned problems.
Tocopherols and their derivatives such as esters for example, are widely used in vitamin supplementation and as antioxidants in the food industry and in many pharmaceutical compositions. However, although in a few cases, a potential use in formulating pharmaceutical compositions has been reported, tocopherols and derivatives thereof have not generally previously been proposed as drug carriers.
Thus for example, European Patent Application No. 539,215 of Stafford-Miller suggests a possible use of Vitamin E and its derivatives as penetration enhancers in topical compositions.
WO 89/03689 of The Liposome Co., describes a liposome system based on acid derivatives of &agr;-tocopherol in a low pH aqueous medium for delivery of drugs which tolerate, or require, acid conditions.
The present invention is based on the surprising observation that tocopherols and derivatives thereof are excellent solvents for drugs which are substantially insoluble or sparingly soluble in water, whilst at the same time having a very low irritative potential for mucosal tissues.
As will be described in more detail below, it has also been found that certain tocopherol derivatives are efficient, non-irritant emulsifiers for such drugs, when dissolved in a tocopherol-based solvent.
In one aspect, the present invention thus provides the use of a tocopherol or a derivative thereof as a solvent and/or emulsifier for substantially insoluble and sparingly soluble biologically active agents, especially in the manufacture of pharmaceutical compositions.
A further aspect of the invention provides a composition for delivery of a substantially insoluble or sparingly soluble biologically active agent, comprising said agent dissolved in a tocopherol or a derivative thereof.
Tocopherols are a range of natural and synthetic compounds, also known by the generic term Vitamin E. &agr;-Tocopherol (chemical name: 2,5,7,8-tetramethyl-2-(4′,8′,12′-trimethyldecyl)-6-chromanole) is the most active and widely distributed in nature, and has been the most widely studied. Other members of the class include beta, gamma, and delta tocopherols but these are not used in pure form in therapeutics, although they are present in foodstuffs. Tocopherols occur in a number of isomeric forms, the D and DL forms being most widely available.
As used herein, the term “tocopherol” includes all such natural and synthetic tocopherol or Vitamin E compounds.
The melting point of natural &agr;-tocopherol is between 2.5 and 3.5° C. &agr;-Tocopherol is a viscous oil at room temperature, is soluble in most organic solvents, but insoluble in water.
Although tocopherols are available naturally in foodstuffs and may be extracted from plants, &agr;-tocopherol is now mainly produced syn
A/S Dumex (Dumex Ltd)
Kipnes Allen R.
Mullis Jeffrey C.
Watov & Kipnes P.C.
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