US3733408A - Flocculated pharmaceutical suspensions - Google Patents

Abstract

DISCLOSED HEREIN ARE STABLE FLOCCULATED SUSPENSIONS OF MEDICAMENTS PREPARED BY COMBINING AN AQUEOUS VEHICLE CONTAINING A NON-IONIC SURFACTANT OF THE POLYETHER TYPE, AND HAVING THE MEDICAMENT DISPERSED THEREIN, AND AN AQUEOUS VEHICLE CONTAINING A MIXTURE OF BENZYL ALCOHOL AND PARABENS, BOTH IN THEIR USUAL PRESERVATIVE AMOUNTS.

Description

United States Patent 3,733,408 FLOCCULATED PHARMACEUTICAL SUSPENSIONS Gunther Storz, Ridgewood, N.Y., assignor to Schering Corporation, Bloomfield, NJ.

No Drawing. Continuation-impart of abandoned application Ser. No. 41,566, May 28, 1970. This application Jan. 12, 1972, Ser. No. 217,298

Int. Cl. A61k 9/00 U.S. Cl. 424-243 9 Claims ABSTRACT OF THE DISCLOSURE Disclosed herein are stable flocculated suspensions of medicaments prepared by combining an aqueous vehicle containing a non-ionic surfactant of the polyether type, and having the medicament dispersed therein, and an aqueous vehicle containing a mixture of benzyl alcohol and parabens, both in their usual preservative amounts.

This application is a continuation-in-part of Ser. No. 41,566, filed May 28, 1970, now abandoned.

This invention relates to novel, pharmaceutically elegant suspensions intended for parenteral, oral, ophthalmic and topical administration. More specifically, this invention relates to the preparation of a formulation, particularly for intramuscular injection, in which the suspended active ingredient is present in flocculated form.

A suspension is generally used to administer medicaments which are relatively insoluble in pharmaceutically acceptable vehicles. A suspension is often the preferred formulation when a slow or prolonged release of the medicament is desired. It may also be the desired form when instability or taste in oral dosage form of a soluble drug presents difficulties to the formulator. Since all suspensions tend to settle in the course of time, it is necessary to redisperse the suspension before administration in order to assure a uniform dosage and, in the case of parenterals, easy withdrawal into a syringe and injection through the hypodermic needle attached thereto. Suspensions vary considerably in their relative ease with which they are redispersed by manual shaking.

In a preferred parenteral suspension, the medicament is present in a flocculated state, i.e. in the form of light, fluffy conglomerates which are held together by weak van der Waals forces. In such a flocculated state, the suspension is more easily redispersed than a non-flocculated suspension. Moreover, a flocculated suspension is more readily dispensed by a syringe, particularly through narrow bore needles.

It is important for such purposes that the degree of flocculation be moderate, i.e. not slight or excessive. If the flocculation is minimal or absent, the particles tend to cake, i.e. form a compacted cake that is relatively dilficult to redisperse. On the other hand, coarsely flocculated suspensions tend to exhibit quick breakup in vials or bottles due to the larger clusters of particles, and physicians generally consider a coarsely flocculated parenteral to be pharmaceutically inelegant and undesirable.

One preparation of such stable flocculated parenterals is described in U.S. Pat. 3,457,348, wherein a hydroxylated preservative is used in substantially higher concentration than normally required for preservative action together with a non-ionic surfactant of the polyether type having oxygen atoms capable of bonding with the hydroxyl moiety of the preservative. The patentees disperse the medicament in the vehicle at the same time that they form the flocculation.

I have now discovered that one can prepare highly stable and easily redispersible flocculated suspensions hav- 3,733,408 Patented May 15, 1973 ing normal levels of hydroxylated preservatives in which the degree of flocculation is moderate and which are characterized by a wide antimicrobial spectrum. These suspensions comprise a water-insoluble medicament, a minor amount up to 1% weight of a pharmaceutically accept able non-ionic surfactant of the polyether type, about 0.5 to 1.5% by weight of benzyl alcohol, and about 0.1 to 0.3% by weight of lower alkyl parabens.

The use of a combination of benzyl alcohol and lower alkyl parabens is surprisingly critical. If one omits the benzyl alcohol from the formulation of this invention, the resulting flocculation is too coarse for physician acceptance. 0n the other hand, if one omits the parabens, the formulation is not sufliciently flocculated and tends to cake. Moreover, the omission of either one diminishes the antimicrobial spectrum, which is a particularly critical feature for parenterals.

The formulations of my invention can be prepared by mixing (a) an aqueous vehicle containing a pharmaceutically acceptable non-ionic surfactant of the polyether type and having dispersed therein at least one solid medicament with (b) an aqueous vehicle containing 0.5 to 1.5% benzyl alcohol and 0.1 to 0.3% lower alkyl parabens. This process involves, of course, the sub-steps of dispersing the water-insoluble medicament in an aqueous vehicle I containing a pharmaceutically acceptable non-ionic surfactant of the polyether type; preparing a separate aqueous vehicle II comprising benzyl alcohol and lower alkyl parabens; (c) mixing vehicles I and II and, if necessary, ((1) adding Water. This procedure readily permits aseptic manufacture, if desired, by aseptically precipitating and collecting the medicament and sterilizing the vehicles as by filtration or autoclaving.

Preferably, the volume of vehicle I represents a minor proportion of the desired final volume, 10%. The medicament should be thoroughly mixed in this vehicle employing a colloid mill or equivalent suitable milling device. In a similarly preferred embodiment, vehicle II represents a major proportion of the desired final volume, In all cases, all the Water should be distilled or otherwise purified, with a particularly high degree of purity for use in preparing parenterals.

The chemical nature of the water-insoluble medicament is not critical with regard to the operability of this invention. This invention will find particular utility in administering steroidal compounds such as betamethasone and dexamethasone and their esters, triamcinolone hexaacetonide, cortisone acetate and prednisolone acetate, as well as non-steroidal water-insoluble medicaments commonly administered by intramuscular and similar routes of injection as, for example, procaine penicillin G.

Similarly, the nature of the pharmaceutically acceptable non-ionic surfactant is not critical as long as it is of the polyether type, i.e., it has oxygen atoms available to bond with the hydroxyl group of the preservative. Suitable materials of this type include the polyethenoxy ethers such as the polyethenoxy mono-esters of alkylphenols as exemplified by polyethenoxy mono-isooctylphenyl ether and the polyethenoxy mono-esters such as polyoxyethylenesorbitan mono-oleate (polysorbate One can also employ higher molecular weight polyethylene glycols (Carbowaxes) and polyoxyethylenepolyoxypropylene block polymers available under the trade name Pluronic polyols.

Various other pharmaceutically acceptable adjuvants may be incorporated into the flocculated suspensions of this invention to the same extent and for the same purpose for which they are incorporated into other parenterals, viz-electrolytes for isotonicity, e.g. sodium chloride; bulfers, e.g. disodium hydrogen phosphate, sodium citrate etc.; chelating agents, e.g. disodium ethylenediaminetetraacetate; stabilizers, e.g. polyethylene glycol 4000, and sorbitol; viscosity control agents, e.g. methylcellulose, sodium carboxymethylcellulose and the like.

The following examples illustrate the preparation of representative fiocculated suspensions according to this invention.

EXAMPLE 1 r 13.2 g. of betamethasone acetate and 3.3 g. of betamethasone sodium phosphate are dispersed in water containing 0.5 g. of polysorbate 80, 0.1 g. of disodium ethylenediaminetetraacetate, 5 g. of sodium chloride, and 2.0 g. of disodium hydrogen phosphate. A second vehicle is prepared containing 9.0 g. of benzyl alcohol, 0.2 g. propylparaben, 1.8 g. methylparaben, and 5.0 g. of sodium carboxymethylcellulose. The first vehicle is mixed with the second vehicle and sufficient water is added to bring the volume up to one liter. The composition is moderately fiocculated.

EXAMPLE 2 12.7 g. of betamethasone dipropionate and 3.3 g. of betamethasone sodium phosphate are dispersed in water containing 5.0 g. sodium chloride, 2.0 g. disodium hydrogen phosphate. 0.4 g. polysorbate 80 and 0.1 g. disodium ethylenediaminetetraacetate. A separate vehicle is prepared containing 20 g. of polyethylene glycol (molecular weight 4000), 9 g. benzyl alcohol, 1.8 g. methylparaben, 0.2 g. propylparaben and 5.0 g. sodium carboxymethylcellulose. The two vehicles are then combined and mixed and sufficient water is added to bring the volume up to one liter. The composition is moderately fiocculated.

The betamethasone-containing flocs of the above examples are very stable and are easily redispersed by manual shaking. They are better protected against a wide variety of potential bacteria and contaminants, (e.g. Bacillus cams) and fungal contaminants, e.g. Aspergillis niger) than if either the benzyl alcohol or parabens were used alone. They exhibit good drainage and can readily be injected intramuscularly through small gauge needles, without blockage of the needle. Moreover, they are visually pharmaceutically elegant and contain only normal levels of hydroxylated preservatives.

Numerous variants of the above-described fiocculated suspensions will be apparent to one skilled in the art within the scope of this invention.

I claim:

1. The method of preparing an easily dispersible, stable, fiocculated suspension of a parenteral medicament maintained in a moderately fiocculated state by weak van der Waals forces comprising mixing (a) an aqueous vehicle containing a pharmaceutically acceptable, non-ionic surfactant of the polyether type and having dispersed therein at least one solid parenteral medicament with (b) an aqueous vehicle containing not more than normal preservative amounts of both benzyl alcohol in the range of 0.5 to 1.5% by weight and lower alkyl parabens in the range of 0.1 to 0.3%, thereby producing a moderately flocculated suspension of said medicament.

2. A method according to claim 1 wherein at least one of said medicaments is a steroid.

3. A method according to claim 1 wherein said lower alkyl parabens comprise both methyl paraben and propyl paraben.

4. A method according to claim 1 wherein at least one of said medicaments is betamethasone or an ester thereof.

5. An aseptic method according to claim 1 wherein prior to mixing, the medicament is aseptically precipitated and both of said vehicles are sterilized.

6. A pharmaceutically elegant, readily redispersible, stable, moderately fiocculated suspension which can be injected intramuscularly through small gauge needles without blockage of the needle, produced in accordance with claim 1, comprising at least one water-insoluble parenteral medicament in a moderately fiocculated state in an aqueous vehicle further containing a minor amount up to 1% by weight of a pharmaceutically acceptable, non-ionic surfactant of the polyether type, and no more than normal preservative amounts in the range of about 0.5 to 1.5% by weight of benzyl alcohol, sufficient to prevent too coarse a composition which clusters particles and about 0.1 to 0.3% by weight of lower alkyl parabens suflicient to prevent a tendency to cake.

7. A fiocculated suspension according to claim 6 wherein at least one of said medicaments is a steroid.

8. A fiocculated suspension according to claim 6 wherein said lower alkyl parabens comprise both methyl parben and propyl paraben.

9. A fiocculated suspension according to claim 8 wherein at least one of said medicaments is betamethasone or an ester thereof.

References Cited UNITED STATES PATENTS 3,457,348 7/1969 Nash et al. 424-229 SHEP K. ROSE, Primary Examiner