Title:  Spheronized self-emulsifying system for hydrophobic and water-sensitive agents

United States Patent:  6,630,150

Issued:  October 7, 2003

Inventors:  Booth; Steven William (Radlett, GB); Clarke; Ashley (Royston, GB); Newton; John Michael (London, GB)

Assignee:  Merck Sharp & Dohme Limited (Hertfordshire, GB)

Appl. No.:  889196

Filed:  October 15, 2001

PCT Filed:  November 1, 2000

PCT NO:  PCT/GB00/00150

PCT PUB.NO.:  WO00/41676

PCT PUB. Date:  July 20, 2000

Abstract

A self-emulsifying system comprises i) microcrystalline cellulose and ii) an oily substance, surfactant, and water is useful for providing solid dosage forms of hydrophobic or water sensitive agents when dried or extruded and spheronized.

SUMMARY OF THE INVENTION

A self-emulsifying system comprises i) microcrystalline cellulose and ii) an oily substance, surfactant, and water is useful for providing solid dosage forms of hydrophobic or water sensitive agents when dried or extruded and spheronised.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a self-emulsifying system which comprises:

I. a first portion comprising microcrystalline cellulose; and

II. a second portion comprising:

(A) up to 200%, based on the weight of the first portion, of an oily substance;

(B) between 2 and 100%, based on the weight of the first portion, of a surfactant; and

(C) between 2 and 1000%, based on the weight of the oily substance and the surfactants, of water;

wherein the total weight of the oily substance and the surfactant is between 2 and 200% of the first portion.

Microcrystalline cellulose is commercially available, for example under the name Avicel.RTM.. The term includes, but is not limited to, pharmaceutical grade microcrystalline cellulose as defined in the British Pharmacopeia. Various grades of microcrystalline cellulose are described in the Handbook of Pharmaceutical Excipients, 2^e, ed. by Wade and Weller, 1994, London and Washington, pages 84 to 87. As an alternative to microcrystalline cellulose powdered cellulose may be used.

Again, the powdered cellulose may be, but is not limited to, pharmaceutical grade. A description of various grades can be found in the above reference at pages 88-90.

The oily substance generally comprises a fatty acid ester or a long chain saturated, partially unsaturated or unsaturated long chain hydrocarbon. Thus the oily substance is preferably a C_1-20 ester of a C_6-30 acid or a C_20-100 hydrocarbon or a mixture thereof.

The C_6-30 acid may be naturally occurring or synthetic and generally contains one, two, three, four or more double bonds, particularly one, two or three double bonds, and may be substituted with one or more hydroxy groups. The C_1-20 ester is the residue of a C_1-20 alcohol comprising one, two or three hydroxy groups, which alcohol may be naturally occurring or synthetic. The acid and ester are generally linear or branched but may contain cyclic portions.

The C_20-100 hydrocarbon is unsaturated, partially saturated or saturated, and is preferably saturated. It may be linear or branched or contain cyclic portions but is preferably linear. It preferably contains 30-80 carbon atoms.

Examples of fatty acids include, but are not limited to, caproic acid, capric acid, caprylic acid, oleic acid, palmoic acid, stearic acid, linoleic acid, octanoic acid, decanoic acid, linolenic acid, palmitic acid, palmitoleic acid, arachidic acid, myristic acid, behenic acid and lignic acid. Mono, di and tri glycerides of these fatty acids are favoured, in particular medium chain mono and diglycerides. Capric acid and caprylic acid are favoured. Naturally occurring vegetable oils such as soyabean oil may be used.

Examples of C_20-100 hydrocarbon are various grades of paraffin.

The surfactant may be any known surfactant which reduces the surface tension of the water or the oily substance thus facilitating mixing. The surfactant may be cationic, anionic, non-ionic or amphoteric. A particularly favoured surfactant is polysorbate 80, generally used at 15-50% w/w. A mixture of surfactants may be used such as polysorbate 80 and span 80. Span 80 is generally used at 5-25% w/w.

The amount of oily substance present is preferably up to 90%, particularly between 5 and 80%, more particularly between 10 and 50%, especially between 20 and 42% of the weight of the first portion.

The amount of surfactant present is preferably between 10 and 90%, particularly between 20 and 80%, and more particularly between 20 and 50% of the weight of the first portion.

The amount of water present is preferably between 2 and 150%, more preferably between 2 and 100%, particularly between 3 and 80%, more particularly between 5 and 60% and especially between 8 and 42% of the weight of oil and surfactant.

The combined weight of the second portion is preferably between 30 and 95% and particularly between 35 and 95% by weight of the first portion and especially between 40 and 90%.

The precise quantities of surfactant, oily substance and water which may be present will depend on the particular nature of these substances.

Specific combinations of oil and surfactant that may be used are: mono and diglycerides USNF (50% w/w) and polysorbate 80 NF (50% w/w); mono and diglycerides USNF (70% w/w), polysorbate 80 NF (20% w/w) and span 80 (10% w/w); and soyabean oil (30%) w/w, polysorbate 80 NF (49% w/w) and span 80 (21% w/w).

The optimal quantities for forming a dosage form, or for making a mixture suitable for extrusion and spheronisation can easily be determined by trial and error using standard equipment. For example if spheronised pellets are desired the mixture will be too wet if an agglomerate is obtained and will be too dry if the particles disintegrate during spheronisation. Nevertheless wetter or drier mixtures may be suitable for drying to powders which may be used for filling or tabletting to produce dosage forms.

In a preferred embodiment the self-emulsifying system further comprises an active agent. The active agent may be, but is not limited to, a pharmaceutical, veterinary product, agrochemical, pesticide, dye or radiochemical. In particular, it is envisaged that the self-emulsifying system may be used to carry any hydrophobic or water sensitive active agent.

In a further embodiment the first portion further comprises a filler. The filler may be any conventional filling material used in various branches of formulation technology, such as lactose or another sugar. Other common fillers are calcium carbonate and glyceryl monostearate. The filler may be present in an amount of 0 to 75% based on the weight of the microcrystalline cellulose, particularly 0 to 50%.

In particular the present invention is surprisingly useful for providing solid dosage forms of hydrophobic or water sensitive active agents.

Accordingly the present invention comprises a mixture comprising:

I. a first portion comprising microcrystalline cellulose and optionally a filler; and

II. a second portion comprising:

(A) up to 200%, based on the weight of the first portion, of an oily substance;

(B) between 2 and 100%, based on the weight of the first portion, of a surfactant;

(C) between 2 and 1000%, based on the weight of the oily substance and the surfactant, of water; and

(D) between 0.1 and 100%, based on the weight of the oily substance and the surfactant, of an active ingredient;

wherein the total weight of the oily substance and the surfactant is between 2 and 200% of the first portion; which mixture is dried.

The active ingredient is preferably present in an amount of between 0.5 and 50%, particularly between 2 and 40%, more particularly between 5 and 25%, based on the weight of the oily substance and surfactant.

The mixture is generally dried at about room temperature to about 60^oC., depending on the nature of the mixture. The drying should be done below a temperature causing degradation of any of the components. Drying is generally carried out until the mixture loses no more water or at least until the mixture is sufficiently dry to process into a solid dosage form. Drying may be carried out on a tray in an oven or by fluidised-bed drying or other conventional methods.

This drying step may be carried out before or after further processing of the mixture. If carried out before processing the dry mixture may be compressed into tablets or used to fill dosage forms.

Alternatively, before drying the mixture may be extruded by conventional means, for example through a 1 mm die. The extrudate may then be dried and compressed into tablets, or spheronised by conventional means before drying with the resulting pellets optionally being compressed into tablets.

The present invention therefore provides a solid dosage form obtainable by drying a mixture comprising:

I. a first portion comprising microcrystalline cellulose and optionally a filler; and

II. a second portion comprising:

(A) up to 200%, based on the weight of the first portion, of an oily substance;

(B) between 2 and 100%, based on the weight of the first portion, of a surfactant;

(C) between 2 and 1000%, based on the weight of the oily substance and the surfactant, of water; and

(D) between 0.1 and 100%, based on the weight of the oily substance and the surfactant, of an active ingredient;

wherein the total weight of the oily substance and the surfactant is between 2 and 200% of the first portion.

In particular the dosage form is a tablet or filled capsule. The filled capsule may be made of soft or hard gelatin, particularly hard gelatin.

Thus the present invention provides a process for making a solid dosage form comprising drying a mixture comprising:

I. a first portion comprising microcrystalline cellulose and optionally a filler; and

II. a second portion comprising:

(A) up to 200%, based on the weight of the first portion, of an oily substance;

(B) between 2 and 100%, based on the weight of the first portion, of a surfactant;

(C) between 2 and 1000%, based on the weight of the oily substance and the surfactant, of water; and

(D) between 0.1 and 100%, based on the weight of the oily substance and the surfactant, of an active ingredient;

wherein the total weight of the oily substance and the surfactant is between 2 and 200% of the first portion; and compressing the dried mixture into a tablet.

There is also provided a process for making a solid dosage form comprising extruding and spheronising a mixture comprising:

I. a first portion comprising microcrystalline cellulose and optionally a filler; and

II. a second portion comprising:

(A) up to 200%, based on the weight of the first portion, of an oily substance;

(B) between 2 and 100%, based on the weight of the first portion, of a surfactant;

(C) between 2 and 1000%, based on the weight of the oily substance and the surfactant, of water; and

(D) between 0.1 and 100%, based on the weight of the oily substance and the surfactant, of an active ingredient;

wherein the total weight of the oily substance and the surfactant is between 2 and 200% of the first portion; drying the spheronised pellets and either filling a capsule with the pellets or compressing the pellets into a tablet.

The same preferred features given above for the mixtures apply to the solid dosage forms also.

The term "spheronised" is intended to refer to pellets which have been processed on spheronisers used in the field of formulation, whether if a suitable size for laboratory or industrial scale processing, or prepared on other devices giving equivalent pellets. Such spheronisers are run at conventional speeds.

Further advantages of the present invention are that the mixture can be extruded at higher pressures than normally possible without clogging or disintegration. Further, the extrudate readily forms spheronised pellets even if the extrudate is prone to initial disintegration. Also the nature of the spheronised pellets is not affected by excess time on the spheroniser after they are formed. Thus the mixture shows excellent handling properties and stability during processing. The dried mixture also demonstrates good stability. In addition the mixtures of the present invention may comprise surprisingly large amounts of oily substance upon addition of a small quantity of water to the wet mixture.

It is understood that self-emulsifying systems other than mono and diglycerides with polysorbate 80 may be used in the present invention, such as those disclosed in WO-A-9119563.

Claim 1 of 14 Claims

What is claimed is:

1. A self-emulsifying system which comprises:

I. a first portion comprising microcrystalline cellulose; and

II. a second portion comprising:

(A) up to 200%, based on the weight of the first portion, of an oily substance;

(B) between 2 and 100%, based on the weight of the first portion, of a surfactant; and

(C) between 2 and 1000%, based on the weight of the oily substance and the surfactants, of water;

wherein the total weight of the oily substance and the surfactant is between 2 and 200% of the first portion.

____________________________________________
If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.