US2897120A - Low viscosity cmc pharmaceutical vehicle - Google Patents

Description

United States Patent G 2,397,120: Low VISCOSITY cMcv VEHICLE Serial; No. 42 ,7; 6 76 Claims.

This inv o e es t nhatmaeeh elzeqm asi, .1 nd. o pa cu ar y lates o, a. y. for improving.t e yr nsee i it a har cteris ic .ofins u lefmediemel s;

One. f h t, d fiieu t. p ob ems a esl P rm elv a t as been the. deteloa h ht Qt sat sfiestoiy e i nso ubl med' insl a en s T is pe l y true for ini e ah si .1. 911. t ieetehle medici al. e t e generally oldn. wo, orms a e dr sewe and as a liquid suspension. The dry powder is designed, for the e emp ran ou pr paration o queolisll i an ia y mmed ate y Pr or to 4. Alifllifi 51. 1161 sion under modern practise. is. sold most frequently in mall o les r m w ic hes sne oh is t ltewn isle a y n e. for mme ie e nie tioa, ash. susaehsion re. also old ai p se r n e ready. or mme iate. se. he d si b P y ic l eheree et s sot shel 3 .52 1.- on. a be e t t o. ate or es; shsseadahi t ear yr nse l tyim r y si enda i itv ia elxes he. p ble of. t in d. te-su n h lehil tyt ant w nger, i y involves dra na n edl fi lqss as sa iteezi ng. h the Plu n the bar e he litit lg ettl ng $31 desirable for several reasons it, causes uneven dos e, ed e clogging. nd elumai a. he. i eel'tehtel e. 1io e m he n o ub medieina ts se tleeht at a l. u o t l is bound o u hth ours q ime; It s. therefore, desirable. t tthe a s uh eise ii he asset be -s p n h en le sha si Qte' se s .s matter of being ableto remove all of the suspe ion from the container in which it is sold and, more importantfrom the syringe from which it is ejected. The suspension should not cling to the walls of e ither 't ype of container nor cloud it in such a Way'as to obscure'the contents thereof or otherwise .give the appearance of 'a contaminated product. Needle clogging isia serious problem for obvious reasons: it increases the'difiiculty; of: making. an injection both from the standpoint of:the patient andjthe person performing the injection; it also, increases, the difiiculty of controlling the dosage-of; themedici a1 agent, administered. i

It is an object of the present invention to providean improved vehicle for suspending. insoluble medi 'nal agents he ieet o he n eseut nv nti e st provide aqueous suspensions of ihsolublen edicinal ma terials which remain suspended, over prolon e peri time. o e e is o Provide sash-susp ns on 6 which are easily syringeable and therefore suitable for ice 2 parenteral injection, Still another object of the present invention is to provide such suspensions which drain cleanly fron1.the container from which they are, dispensed, will not clog; the needle of the hypodermic syringe, have 1 littlegtentlency to settle out after. prolonged storage, and

are. easily. resuspended with gentle shaking whensettling doesoccur. Other objects willbe apparent to. one skilled in the art to which this invention pertains.

These objects are accomplished in the present invention. by. the use of a combination of hydrophilic poly.-

vinyl. compound, such as polyvinyl pyrollidone, polyvinyl alcohol, or mixtures. thereof, and a low viscosity alkaline salt of carboxymethycellulose in an aqueous vehicle asthe dispersion. medium for. insoluble medicinal materials, By, means of. this combination, suspensions of insoluble, medicinal materials lacking the undesirable. charaeteristics set forth, above are obtained.

Although, itis known that sodium carboxymethylcelluloseisa useful suspending agentfor procaine penicillin G, it is belieyed. that the combination. with hydrophilic polyvinyl compounds has. never been used prior to, the.

present invention or has there been any suggestion that,

the combination would; possess unexpected advantages v not attributable, to, either alone. For example, sodium ar xymethyl llulose when used with procaine, p enjcillin is helpful inproducing a suspension; but it. doesnot drain we1lffrom a container, especially a hypodermiesyringe. IfuSed. in great enough quantity to suspend PiQCaine penicillin satisfactorily, the viscQSi y inCrQases tq. an extent. such that the drainage problem results, How ever. he, ac i n of sodium. r oxme hyl ll lo e as a u pen n agen i u predi able n e i is entirely un atisfa t ry When-us to u pend u h-ma als aseq tir. eeeetateltho h su h a u ensi n. a s W l from. a bot le ontrary to the ase o p c ne P l llin su pe si n). pack g occurs an a un fo m r suspensionis unobtainable. When used with hydrocortisone a suspension wa produ e i h. wa po y di persed and drained poorly. With hydrocortisone acetate, the resuit was similar. When po y in l p r l do s us d aloneas a suspending agent. for procaine penicillin, packingand settlingoccurs although drainage is good; On the. other handwhen it is used in combination with cortisone acetate it not only, sometimes causes hard packing, but t e ot les r po lya d a uniform suspensi n s not obtainable at some temperatures. When used to u p n hudr sort pne P lyvi pyr id e d o u e. m peeking; sad d aina e s ly fair- W th y re t on e e P l viny p f l s n pie duces a hard cake which cannot be suspended. In view of these inconsistencies in the results obtained by the s o he uspe din agent with fe e t s e i is truly remarkable that the combination of these materials produc es consistently good results when used as a. i nentl ns medium or h materials ti n d s. e as ther njs'o ubleme e e a n Since very little, is known about the mechanics of making suspensions suitable for therapeutic use, and since the action of the, individual materials is wholly unpre polyvinyl pytrolidone or polyvinyl alcohol or a mixture of the two or like hydrophilic polyvinyl compounds, with a low viscosity alkaline salt of carboxyrnethylcellulose would give markedly superior suspensions. The superior suspending properties of such combinations of hydrophilic polyvinyl compounds and a low viscosity alkaline salt of carboxymethylcellulose, coupled with other factors which complement or enhance the suspending action of the combination, such as the particle size of the insoluble materials utilized, the pH of the vehicle, the viscosity of the vehicle, the coatings on the insoluble medicinal agents involved, the amount of insoluble medicinal agent uti lized, the coating on the bottles or containers from which the suspension is to be dispensed, and the preservative used Where the suspension must be sterile for parenteral administration, provide suspensions suitable for therapeutic use which avoid ditficulties heretofore encountered in the prior art.

The present invention, therefore, is directed broadly to the use of a combination of a hydrophilic polyvinyl compound, such as polyvinyl pyrrolidone, polyvinyl alcohol, and mixtures thereof, and a low viscosity alkaline salt of carboxyrnethylcellulose, such as the low viscosity sodium and other alkali metal salts of carboxymethylcellulose, as a suspending agent for an insoluble medicinal agent in an aqueous vehicle and more particularly to combinations embodying various of the other factors noted above as will be more particularly set forth hereinafter.

One of the more important factors which may be used to complement or enhance the combination suspending agent of the invention is the viscosity of the suspension. Thus it has been found advantageous in preparing suspensions according to the invention to maintain a viscosity of about fifteen to about eighty centipoises at room temperature and that optimum results are obtained ordinarily with a viscosity between about twenty and forty centipoises at room temperature. While several factors aifect the viscosity of the suspensions, the amount of the hydrophilic polyvinyl compound, the amount of the low viscosity alkaline salt of carboxymethylcellulose, and the amount and character of the active material, that is, the insoluble medicinal agent which is to be suspended, and while the viscosity can sometimes be affected by the addition of surface-active agents and deflocculating agents, suitable viscosities are ordinarily obtained by the use of from about 0.1 to about three percent of polyvinyl pyrrolidone (percentages here weight by volume unless otherwise specified), and about 0.1 to about one percent of a low viscosity alkali salt of carboxymethylcellulose.

The term low voscosity alkaline salt of carboxymethylcellulose is used herein to designate those alkali carboxymethylcelluloses, such as sodium carboxymethylcellulose, which have a viscosity in two percent aqueous solution of less than about 100 centipoises and advantageously between about 25 and fifty centipoises at 25 degrees centigrade using a Brookfield Viscometer Model LVF. Thus by combining between about 300,000 and about 600,000 units of procaine penicillin per milliliter of suspension, advantageously about 500,000 units per milliliter, with about 0.5 percent polyvinyl pyrrolidone and about 0.5 percent of low viscosity sodium carboxymethylcellulose, there are obtained suspensions which when prepared aseptically are particularly well suited for parenteral use and which can be injected through a hypodermic needle without the disadvantages heretofore encountered in this art.

It is most advantageous to use fifty percent of micronized procaine penicillin having a particle size ranging from two to ten microns together with fifty percent milled procaine penicillin with a particle size ranging from forty to sixty microns. The exact reason for the improved suspensions obtained by using particles of varying sizes is not know but some observations regarding the properties of such suspensions have been made. For example,

crease the viscosity of the vehicle and tend to form aggregates or globules of the active ingredient. When all particles are of the same size, they seem to have a greater tendency to pack. When the suspension is prepared for injection through a syringe, the use of particles of the same size tends to create a sort of log jam when passing through the needle. There seemsto be a lesser tendency to block a needle when the particles are of varying sizes. It has been observed that eighteen to 26 gauge needles can be used when the particles are of the varying sizes indicated. Of course, it is not absolutely essential to the present invention to have varying particle sizes of between about two to sixty microns of the active medicinal agent to be suspended, 'but more consistent results will be obtained if varying particle sizes are used.

Further improvement is obtained by coating the insoluble material to be suspended with a phospholipid, such as lecithin, cephalin and the like. This is the subject matter of copending application Serial Number 108,419, filed August 3, 1949, now Patent Number 2,694,665, issued November 16, 1954. Thus lecithin coating has been successfully utilized on procaine penicillin. Although the role of the phospholipid as a coating for the insoluble medicinal agent in the compositions of the present invention is more fully explained in the copending application indicated, it should be noted that such coated materials contribute much to the success of suspensions such as dealt with in the present invention. Besides contributing to the overall qualities of the suspension, a phospholipid coating seems to act as a sort of dispersing agent for the insoluble medicinal agent. Without such a coating procaine penicillin particles, for example, do not wet properly. However, any such observation as to the contribution of lecithin to the preparation of a successful suspension will not withstand critical scrutiny. It is only important to note that lecithin does contribute to the overall success of the suspension, both as an individual ingredient and in combination with the other materials indicated.

Depending upon the nature of the insoluble medicinal agent to be suspended, it may prove desirable to utilize a buffer to control the pH of the suspension within a desired range. For example, it is desirable to use sodium citrate where procaine penicillin, cortisone acetate, hydrocortisone, hydrocortisone acetate and similar materials are to be suspended. For procaine penicillin it is desirable to use sufiicient buffer to keep the supension close to but below a pH of about 7, that is between about 5 and about 7. It should also be noted that the pH may change upon storage depending upon the temperature. For example, if the pH starts out at about 6.3 to 6.5, it will probably go down to about 5.5 to 5.8 upon storage at room temperature for any considerable length of time.

Further improvement for the suspensions of the present invention can be obtained by the use of silicone coated bottles as containers therefor. These tend to impart proper Wetting characteristics to the surface of glass from which such suspensions are dispensed. From this standpoint it should be noted that the vehicle of the present invention works in a very satisfactory manner, in silicone coated bottles, while vehicles containing such surface active materials as Tween (a polyoxyethylene ether of a partial higher fatty acid ester of sorbitan) so affect the silicone coating as to give undesirable results. For example, a silicone coated bottle containing such a surface active agent causes a haze in the bottle and clouds it in such a way as to obscure its contents, tends to indicate poor drainage, or give the impression of a contaminated product.

When the suspensions of the present invention are utilized for sterile purposes, such as for parenteral injection, it is desirable to utilize a preservative such as methyl, propyl, or butyl parabens. Although such preservatives do not contribute anything to the suspension of insoluble medicinal agents, they are also not adversely affected by the vehicle utilized in the present invention.

The phrase procaine penicillin :is used. in the present specification in a generic 'senseand is intendedto include the various forms of penicillin, such as G, O, K and the like, as well as other derivativesof procaine, such as 2- chloroprocaine, which are capable of forming insoluble salts with penicillin. Likewise other insoluble penicillin salts such as N,N-dibenzylethylenediamine-penicillin, me successfully suspended by the vehicle-of the present invention. v e g It will be apparent from the foregoing-that a considerable number of variables can and are involved in-"preparing successful suspensions such as contemplated by the present invention. Numerous experiments have been conducted in an'attempt" to'a'djust'the' variables "to prepare the most successful product. While there is little doubt that the basic combination of a hydrophilic polyvinyl compound and a low viscosity alkaline salt of carboxymethylcellulose is the most important brfundamental factor in the present inventionythe other factors indicated are definite improvements thereof, I

Among the numerous experiments conducted'with the vehicle of the present invention are the following, presented in summarized form:

Materials used Results obtained Vehicles of various concentrations plus procaine penicillin G were evaluated on the basis of suspend- ,ing quality and drainage in silicone treated bottles; and'the results indicated that suspensions withsodium'carboxymethylcelliilose alone did not drain as well asjsuspensions with sodium carboxymethylcellu- ,lose (CMC) and polyvinyl pyrroli- Comparison of sodium carboxy methylcellulose (0M0) of difierent viscosities, high, medium, low, with theaddition of polyvinyl pyrrolidone (PVP) at one percent concentration.

0M0 was suitable Resuspending qualities ,of suspensions made with vehicle containing PVP without 0M0 were generally Comparison of various combinations of procaine penicillin G 300,000 units/cc. and PVP vehicles (1%). v

suspendabilityythan those suspensions made with CMC and PVP.

Resultant suspension would not Aqueous suspension of 2-chloro- I readily resuspend.

procaine penicillin 0 300,000 units/cc. and PVP vehicle Aqueous suspension of procaine penicillin G 300,000 units/cc. in PVP vehicle (1%).

Aqueous suspension of procaine penicillin G 500,000 units/cc. in PVP vehicle (1%).

Aqueous suspension of procaine penicillin G 500,000 units/cc. in

PVP (1%)- V" CMC (0.2%)

vehicle.

1,000,000, unit vial of procaine penicillin G (800,000 units) and sodium penicillin G (200,000

units) with 0.5% LV CMC and 0.6% PVP.

Aqueous suspension of procaine penicillin G 300,000 units/cc. in 1% PVP vehicle.

Aqueous suspension of procaine penicillin G 300,000 units/ccL'in avg (1%) and LV CMC Aqueous suspension of procaine penicillin G 300,000 units/cc. in LV 0M0 (0.5%) vehicle. 1

Various suspensions using PVP alone, LV CMC alone, and PVP LV 0M0.

Viscosity of this suspension was low and the material settled out and packed.

This suspension had a low. viscosity 'jand'good drainage and resuspendability.

Viscosity of this suspension was high (l28cps.) and gave poordrainage.

Various suspensions in vials. have been shipped from Kalamazoo,

neapolis and Atlanta -by" train, plane, and truck. Evaluation of samples on return shows that the PVP-LV 0M0 vehicle gives a j product with good drainage, good resuspendobilitm'and good syringeability while neither PVP alone nor CMC alone does.

*Low viscosity material which at 2%. concentration in aqueous solution has a viscosity of 25 to'50 centip'oises at 25 C.

PVP is, of course, an abbreviation for polyvinylpyrrolidone, while CMC is an abbreviation for sodium cardone '(PVP) only low viscosity.

poorer (packing, settling, and re- Michigan to Los Angeles; Min-" boxymethylcellulose. Similar results are obtained by us ing polyvinyl alcohol and other alkaline salts of carbonmethylcellulose.

The polyvinyl hydrophilic compounds of the invention are"of"pharrnaceutical .g'raas, non-toxic, inert and capable of being sterilized without change in composition. the addition bfwater to a drycom'p'osition contain'ing a steroid and-the selected hydrophiliepolyvinyl compound, followed by m'ixingfa stable steroid suspension is readily obtained.

The polyvinyl pyrrolidone used in the compositions described herein is soldby-the'General Aniline and Film Company under the trademark Plasdone and 'is characterized by a viscosity coeflicient, i.e., K value, of 26 to '36 and a molecularweight of-abeur'wnoo. 'However, 'itis to be understood that theinvention is-not to be limited to the use of this specific polyvinyl pyrrolidone since other equivalent'polyvinyl pyrrolidon'es of pharmaceutical grade are likewise suitable. -While "a polyvinyl pyrrolidone "of pharmaceutical grade possessing a molecular weight between twenty. and eighty thousand is preferred, satisfactory results arealso'obtainedby the use of a polyvinyl pyrrolidone outside of this molecular "weight range.

viscosity of four to'six'centipoises (four percentl aquieous solution at twenty degrees centigrade), a pH of six to eight and a 86 to'89 percenthydrolysis from polyvinyl acetate. It is to' be understood, however, that;th e"inventionis notl imitedto the'use of this specific-polyvinyl alcohol since any" other"equivalent polyvinyl alcohol of pharmaceutical 'grade can likewise be used to achieve similar results.

Similar experiments and similar resultsh'avefbe'en obtained'with the basic combinationof-"a hydrophilic-polyvinyl compound with a low viscosity'alkaline salt'of carboxymethylcellulose in an "aqueous vehicle a for other insoluble medicinal agents. For example, thefollowing tables-demonstratethe use of the-aforesaid'vehicle for various steroids such as cortisone acetate,hydrocortisone, and'hydrocortisone acetate. 'The vehicles are rated in the tables by anarbitra'ry scale ranging from 0 to 4+. The preparations were graded for such characteristics as appearance, resuspendability, syringeab ility, drainage and changes in particle size. A preparation with'an 0 rating is entirely unacceptableand indicates physical instability on short term storage-at various temperatures. A 4+ preparation has the best-physical characteristics of the'm'aterials listed in the' tables. 'Values'of l +fto 3+ were assigned to preparations falling in between thes'e two extremes. Suspensions rated l+-or 2+ are-not regardedas-satisfactory for commercial purposes. "A composite evaluation of samples stored at fortydegrees centi'grade, 25 degrees centigrade, and four degrees centigrade was m ade, and the rating assigned to the'whole group. Pertinent remarks are included under the heading comments. It will be noted that'variousTamounts'of polyvinyl pyrrolidone and low viscosity sodium c'arboxymethylcellulose we're used.

Other materials (e.g., buifers, preservatives, surface active agents, and'the like)"-were also included to determine their' efiect upon the suspension. Where type-of particle is not stated it is tojbe understood that a precipitated or crystalline product was used. The term sodium j CMC L.V.refers to sodium carboxymethylcellilldse having a viscosity in 2% aqueous solution of 25 to 50 centipoisesat 25 degrees centigiade. The term sodium CMC Hy. refers to; sodium carboxymethylcellulose havinga viscosity in 1f'% aqueoussolu'tionbf j13'00"'to 2200 centipoises at 25 degrees lcentigra'de. In Table I except, where otherwise indicated, 'the suspension contained percer1-t sodium citrate arid :0326 percent inethylparaben. -All amounts are indicated in percentages.

8 TABLE I Suspensions prepared from different lots of cortisone acetate Percentage composition Evaluation of suspension Good.

25 good. 40 and 4 slight packing but resuspends O.K. Color increasing all temp. Initial color of cortisone acetate not good.

Good. 0.9% sodium chloride in place of 0.57% sodium citrate and 0.18%

methyl and 0.02% propylparaben in place of 0.26% methylparaben.

80- Comments Drug and cone. PVP dium 1 mo. 3 mos. 6 mos.

M0 L.V.

Lot 1, 10.0 0. 0 Hard packing. Uniform resuspension not obtainable at 4 and Bottles 0 5 drajined poorly. (Silicone coated bottles.)

- 0. 5 Packing at 4, some at 25. Bottles drained well.

5 Packing at 4. Uniform resuspension could not be obtained. 25 and better. Bottles drained well. 0.5 5 25 and 40 resuspends best. All resuspended uniformly easily. Bottles drained'we 0. 5 5 Good-a1l temperatures. 0. 75 4 0. Crystal growth. 25--best. 0. 75 75 4Crystal growth-1 mo. 25 and 40-satisfactory. 0. 75 25Crystal growth3 mos. 4, 40 very good. Lot 5, 2 5 0. 75 Slight paokingresuspends O.K. Lot 6, micronized, 2.5 0. 75 Good. Lot 7, micronized, 2.5 0. 75 Do. Lot 8, micronized, 2 0. 75 Do.

, 0. 75 Good. 0.15% methyl and 0.02% propylparaben used in place of 0.26%

methylparaben. Lot 5, 2.5 0. Slight packing-3 mos. Resuspends O.K. Lot 8, micro 0. 25-Best. Lot 1, 2.5 0. Slight eaking. Resuspends. Lot 2, micronized, 0. 4 crystal growth-3 mos. 25 best, no growth. 40 packing, but suspends. Lot 4, micronized, 2. 0. Good. Lot 6, micronized, 2 5 0. D Lot 7, microm'zed, 2 0. Do.

Lot 10, micronized,

coated, 10.0.

Lot 10, micronized, 10.0 Lot 2, micronized 10.0"

The different lots of cortisone acet given in Table I shows therefore that the combination suspending agent or dispersion medium of the invention can be used to sodium citrate. 25 and 40-better than 4 C.

25 ar]1)d 40 better than 4 0.

No sodium citrate.

25 and 40 better than 4 C.

25 and 40 better than 4 0.

ate are representative of difiercnt preparations having different particle type sions of a wide variety of difierent forms of cortisone acetate.

Do. 40 better than 4 and 25. No Sodium citrate.

Excessifive foam-4 best. 0.57% sodium chloride in place of 0.57% sodium 0 re e. 4 and 25better than 40 C. 0.4% sodium 0M0, HV in place of 0.57%

4 and 25better than 40 0. Bottles dont drain well.

Do. 25 and 40 better than 4 C. 0.2% sodium CMC, EV.

s and crystal structures.

The data prepare acceptable suspen- TABLE II S uspenszons of hydrocortzsone acetate Percentage composition Evaluation of suspensions Hydro- Sodium Sodium Comments corti- PVP OMO Sodium chlo- Preservative 1 mo. 3 mos. Gmos. sone LV citrate ride acetate 2 5.. 0. 5 0 5 0.9 0.01 thimerosal Agglomerated particles. Suspend O.K.

1.0% Propylene glycol. 2 5 0.1 0 5 0.9 0.1 thimerosal Particles not entirely wetted by vehicle. 0.1% Tween 80. 2.5. 0 1 0.9 0.26 methylparaben 0 Viscosity too great. Unable to resuspend. 0.5% sodium 0M0 H.V., 0.2% Pluronie F68. 0. 75 0. 75 0.57 Oaking. Difliculty in resuspension. 0.1 0. 75 0.9 Cakingunable to resuspend. 0.2%

Pluronic F68. 0.5 0.5 0.9 Slight caking. Resuspends O.K. 0. 5 0. 5 0. 57 Good, all temperatures. 0. 5 0.57 Hard cake. Unable to suspend. 0. 5 0. 57 Agglomerated, poor d1ainagepoor dispersion of solids. 0. 75 0.75 0.57 00d. 0. 75 0. 75 0.9 Slight shaking. Resuspend O.K. 0. 75 0.75 0.5 0.7 0. 5 0. 75 0.5 0. 7 0.1 0. 75 0.5 0.7 0.5 0.5 0.5 0.7 Slighitl tendency to cake. Resuspcnds eas y. 0. 1 0. 5 0. 5 0. 7 do Particle not entirely wetted by vehicle. 0. 1 0. 5 0. 9 0.1 thimerosal 0 Caking, clumping, foam. 0.1% Pluronic F68. 0. 1 0.3 0.9 0.1 methyIpara-ben Slight haze in vehicle.

and 0.02 propylparaben. 0.2 0.3 0.9 0.18 methyl and 0.02 Slight film of solids on walls of glass.

propylparaben. 0. 3 0.3 0. 9 do Do. 0.1 o. 4 0. 9 Do. 0.2 0.4 0.9 Do.

q UTABLE III Suspension of hydrocortiso r'ie Percentage composition Evaluation ofsuspehsldns 1 Sodium,

chloride PVT Preservatlv e Comments 1 mo. 3 mo. 6mo.

00. 0 reveem vuoncnrqvcnqqq lcnm UIU'I O'IUIU! Q'l 00. 0 0000010000000 00. 0 'usmeew w mmorQqqQmrkrqw- Ormmcn more: a

00000 00000000 osowco The, following, examplesiare positions and processyofnhepresent invention but are not to be construed as limiting.

A sterile suspension. containing 2300,000 id, ocaine penicillin G in each cubic centimeter'is prepared as follows:

Each cc. of the vehicle contains Water of injection, suflicienfto 'niake up li0'cc.

The sodium citrate, sodium canboxymethylcellulose and the Plasdone are mixed in sufficient water for injection and sterilized by heating to 120 degrees centigrade, for thirty minutes. When the vehicle .has cooled, the sterile methylparaben is added. The methylparaben is ethylene oxide or formaldehyde sterilized.

The final suspension. is prepared as follows:

Each cc. of :the suspension contains- 157,500 units sterile :bulk procaine penicillin .G milled (4% lecithin coated) v 157,500 units sterile bulk procaine penicillin G micronized 1.25% lecithin Q.s. sterile vehicle (as prepared above) The sterile bulk procaine penicillin :G, milled ;(4% lecithin coated) and the sterile .bulk procaine. penicillin G, micronized (1.25% lecithin coated) are sterilized by treatment with ethylene oxide. This done before. the lecithin coating is applied. After the penicillin isethylene oxide sterilized, it.is handled aseptically. The sterile milled and micronized penicillins are added under aseptic conditions, and the sterile suspension is passed through a colloid mill and filled aseptically into sterile containers.

It should be noted that micronizing produces,.;p.ar ticle sizes of about two to ten microns, and milling The lecithin coating is carried out as -disclosed in Us. application Serial Number 108,419, filed August 3, 1949.

0.26 methylpraben- 0.18- methyl and 0.02 t

prgpylparaben. 0

' Sllghfcakin'g'at 40,3n'1os. Resuspends O.K. 0.2% -Pluronic1FB8. Re airing at 25 and 4. Drainage only a r. Agglomerated poor dispersion of solids.

imswoon Slight cakmg onstopper.

. Some agglomeration. 40, 3 mos gummy mass.

resuspend. rei s 1r-- Drailrjiegefainfbest.

o. 1 Slight filni of sollds sticks to wells.

So'nieagglomeration.

Deme er;w n -Sllght caking tendencyalter 3 mos.

Someagglomeration. .Dre n se i Soineagglomeretion. Slight-,filmof solids sticks to walls.

' 0.1%"P1uronlc'F68.

V Slight film of solids sticks to walls.

I Unable I to produces gparticle ranging from forty to sixty microns. y v

. EWP v A sterile suspension eontain'ing 3 00,000junitsof procaine penicillin G in each cubic centimeter is prepared as follows: H p

' Eaiili' 60. 6f the vehio1e contains- Water for injection, sufficient to make up 1.0 cc.

Theso diurn nitrate, sodium canboxymethylcellulose and h Bast ns 'ar tmix d in s fi i nt Wa inj t and sterilized by -'heating to degrees centi-grade for hi y mi ute the-w isk has co e t est i m h n rahene d th i e p opy p a n are added- The final suspensipn spreparedas follows:

Each cc. of the suspension contains 157,500 units ste'rile Biilkpr0caine'penicillin -G =rnilled (4% lecithin coated) U 157,500 units, .sterile =l ulk procaine penicillin G micronized' 1.25% lecithin) H Q.s."s'terile'vhicle "(as prepared above) The sterile milled and micronized penicillins are added to suflieient sterile yehicle in a sterile container and mixed well. "The st'erilesuspension is' fpa'ssed through acolloidmill. H

EXAMPLE 3 A sterile suspension containing 500,000 units of jprocaine penicillin G in teach cubiecentim'eter. is prepared s qwsa.

Each cc. of the vehicle contains- Sodium citr ranular, U.S,.P .5.7 Sodium carboiryrne'thylcellulose, low viscosity 2.0 Plasdonef(polyvinyl'fpyrrolidone) "10.0 Sterile metnmpir ben, s,P 1.5 sterile pifopylpara ben 0.2

Water for injection; 'st'ffliei ent 15 551;

The sodium citrate, sodium carboxymethylcellulos and the Plasdone are mixed in sufficient water for injection and sterilized by heating to 120 degrees centigrade for thirty minutes. When the vehicle has cooled, the sterile methylparaben and sterile propylparaben are added.

The final suspension is prepared as follows:

Each cc. of the suspension contains- 382,500 units sterile bulk procaine penicillin G, milled (1.25% lecithin) 127,500 units sterile bulk procaine penicillin G micronized (1.25% lecithin) Q.s. sterile vehicle (as prepared above) EXAMPLE Following the procedure of Example 3, a suspension of cortisone acetate is prepared by substituting 25 milligrams per cubic centimeter of cortisone acetate (precipitated or micronized) for the procaine penicillin to produce a suspension possessing excellent physical stability and good syringeability characteristics.

Good suspensions of cortisone acetate can also be formed by omitting the lecithin coating.

EXAMPLE 6 Following the procedure of Example 3, a suspension of hydrocortisone is prepared by substituting fifteen milligrams per cubic centimeter of hydrocortisone (milled or precipitated) for the procaine penicillin to produce a suspension possessing excellent physical stability and good syringeability characteristics.

Good suspensions of hydrocortisone can also be obtained by omitting the lecithin coating.

EXAMPLE 7 Following the procedure of Example 3, a suspension of hydrocortisone acetate is prepared by substituting fifteen milligrams per cubic centimeter of hydrocortisone acetate (milled or precipitated) for the procaine penicillin to produce a suspension possessing excellent physical stability and good syringeability characteristics.

Good suspensions of hydrocortisone acetate can also be obtained by omitting the lecithin coating.

EXAMPLE 8 A sterile powder containing 800,000 units of procaine penicillin G and 200,000 units of sodium penicillin G can be prepared as follows:

Each vial contains 675,000 units sterile bulk procaine penicillin G (4% lecithin coated) 225,000 units sterile micronized crystalline procaine penicillin G 300,000 units sterile crystalline pencillin G, sodium milled 7 mg. sterile sodium citrate, granular, U.S.P.

5.6 mg. sterile sodium carboxymethylcellulose, low viscosity 5.6 mg. sterile Plasdone (polyvinyl pyrrolidone) The powders are sterilized separately by treatment with ethylene oxide and then blended in a suitable sterile blender and packaged in a sterile bottle. On addition of one cubic centimeter of sterile water a satisfactory suspension for parenteral use is obtained on shaking.

Numerous other compositions embodying the vehicle of the present invention can be prepared. Many of these are illustrated in the various tables and general descriptive matter in the present specification. Most of the specific examples are directed to parenterals. The necessity for good suspensions in that field is very acute. However, good suspensions are also important in other pharmaceutical preparations, such as liquid oral preparations ophthalmic preparations, sprays, lotions, and the like. These can be prepared in the vehicle of the present invention by using conventional pharmaceutical techniques.

Likewise the specific insoluble medicinal agents included in the specific examples are illustrative only, since the vehicle of the present invention is equally efiective with many other such medicinals, for example, progesterone, testosterone propionate, estradiol monobenzoate, sultamerazine, sulfadiazine, sulfamethazine, aluminum salts of p-aminobenzenesulfonamides, complex aluminum salts of penicillin and p-aminobenzenesulfonamides, riboflavin, barbiturates (e.g., phenobarbital), salicylamide, and the like.

It is to be understood that the invention is not to be limited to the exact details of operation or exact compositions shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims.

We claim:

1. An aqueous vehicle for insoluble medicinal agents comprising about 0.1 to about one percent of a low viscosity alkaline salt of carboxymethylcellulose and about 0.1 to about three percent of a hydrophilic polyvinyl compound selected from the group consisting of polyvinyl pyrrolidone and polyvinyl alcohol.

2. An aqueous vehicle for insoluble medicinal agents comprising from about 0.1 to about one percent of low viscosity sodium carboxymethylcellulose and about 0.1 to about three percent of polyvinyl pyrrolidone.

3. An aqueous vehicle for insoluble medicinal agents comprising about 0.5 percent of low viscosity sodium carboxymethylcellulose and about 0.5 percent of polyvinyl pyrrolidone.

4. A composition of matter comprising an insoluble medicinal agent and from about 0.1 to about one percent of low viscosity sodium carboxymethylcellulose and about 0.1 to about three percent of polyvinyl pyrrolidone.

5. A composition of matter comprising procaine penicillin and from about 0.1 to about one percent of low viscosity sodium carboxymethylcellulose and about 0.1 to about three percent of polyvinyl pyrrolidone.

6. A composition of matter comprising an insoluble steroid and from about 0.1 to one percent of low viscosity sodium carboxymethylcellulose and about 0.1 to three percent of polyvinyl pyrrolidone.

7. Product of claim 6 wherein the insoluble steroid is cortisone acetate.

8. Product of claim 6 wherein the insoluble steroid is hydrocortisone.

9. Product of claim 6 wherein the insoluble steroid is hydrocortisone acetate.

10. An aqueous dispersion medium for insoluble medicinal agents comprising minor proportions of low viscosity sodium carboxymethylcellulose and polyvinyl pyrrolidone in such amounts as to maintain a viscosity between about fifteen and eighty centipoises at 25 degrees centigrade.

11. An aqueous dispersion medium for insoluble medicinal agents comprising minor proportions of low viscosity sodium carboxymethylcellulose and polyvinyl pyrrolidone in such amounts as to maintain a viscosity between about twenty and forty centipoises at 25 degrees centigrade.

12. A therapeutic composition in an injectable aqueous vehicle having a viscosity between about fifteen and eighty centipoises comprising low viscosity sodium carboxymethylcellulose, polyvinyl pyrrolidone, a buffer,

and procaine penicillin coated at least in part with lecithin.

13. A therapeutic composition in an injectable aqueous vehicle comprising about 0.1 to one percent of low viscosity sodium carboxymethylcellulose, about 0.1 to three percent polyvinyl pyrrolidone, and procaine penicillin of particle sizes ranging from about two to sixty microns and coated at least in part with lecithin.

14. A therapeutic composition in an injectable aqueous vehicle to be dispensed from a silicone coated glass container, having a pH between about and 7 and a viscosity between about fifteen and eighty centipoises, which composition comprises a preservative, a bufier, a member selected from the group consisting of polyvinyl pyrrolidone and polyvinyl alcohol, a low viscosity alkaline salt of carboxymethylcellulose, and from about 300,000 to 600,000 units per cubic centimeter of procaine penicillin in varying particle sizes ranging from about two to sixty microns and coated at least in part with lecithin.

15. A therapeutic composition in an injectable aqueous vehicle to be dispensed from a silicone coated glass container having a pH between about 6.5 and 6.8 and a viscosity between about twenty and forty centipoises, which composition comprises a member selected from the group consisting of methyl, propyl and butyl parabens, sodium citrate, from about 0.1 to about three percent of polyvinyl pyrrolidone, between about 0.1 and about one percent of low viscosity sodium carboxymethylcellulose, and from about 300,000 to 600,000 units per cubic centimeter of procaine penicillin in varying sizes ranging from about two to sixty microns and coated at least in part with lecithin.

16. A dry composition for the extemporaneous preparation of an aqueous fluid which composition comprises a low viscosity alkaline salt of carboxymethylcellulose and a member selected from the group consisting of polyvinyl pyrrolidone and polyvinyl alcohol, in the proportions of about 0.1 to 1 to about 0.1 to 3, and an insoluble medicinal agent.

17. A dry composition for the extemporaneous preparation of an aqueous fluid which composition comprises from about 0.1 to about one part of a low viscosity alkaline salt of carboxymethylcellulose, from about 0.1 to about three parts of a member selected from the group consisting of polyvinyl pyrrolidone and polyvinyl alcohol, and an insoluble medicinal agent, characterized in that on shaking with about 100 parts of water an aqueous suspension having a viscosity between about fifteen and eighty centipoises at 25 degrees centigrade is produced.

18. A composition of matter comprising a water-insoluble medicinal agent having approximately equivalent portions of particles from about two to about ten microns and particles from about forty to about sixty microns, at least a partial lecithin coating on said particles, from about 0.1 to about one percent of low viscosity sodium carboxymethylcellulose, and from about 0.1 to about three percent of a hydrophilic polyvinyl compound selected from the group consisting of polyvinyl pyrrolidone and polyvinyl alcohol.

19. An injectable aqueous suspension having a viscosity between about fifteen and eighty centipoises at 25 degrees centigrade and comprising a water-insoluble medicinal agent 'having approximately equivalent portions of particles from about two to about ten microns and particles from about forty to about sixty microns, at least a partial lecithin coating on said particles, low viscosity sodium carboxymethylcellulose and a hydrophilic polyvinyl compound selected from the group consisting of polyvinyl pyrrolidone and polyvinyl alcohol.

20. An injectable aqueous suspension having a viscosity of between about twenty and about forty centipoises at 25 degrees centigrade and comprising a water-insoluble medicinal agent having approximately equivalent portions of particles from about two to about ten microns and particles from about forty to about sixty microns, at least a partial lecithin coating on said particles, from about 0.1 to about one percent of low viscosity sodium carboxymethylcellulose, and from about 0.1 to about three percent of a hydrophilic polyvinyl compound selected from the group consisting of polyvinyl pyrrolidone and polyvinyl alcohol.

References Cited in the file of this patent UNITED STATES PATENTS 2,637,679 Gaunt May 5, 1953 2,650,217 Macek Aug. 25, 1953 2,671,749 Schultz Mar. 9, 1954 2,671,750 Macek Mar. 9, 1954 2,741,573 Kirchmeyer et al. Apr. 10, 1956 2,793,156 Souler May 21, 1957 FOREIGN PATENTS 1,060,811 France Apr. 6, 1954 880,046 Germany June 18, 1953 OTHER REFERENCES Mantell: Water Soluble Gums, Reinhold Pub. Co., N.Y., 1947, pp. 152-155.

Janot: Les Penicillines a Action Prolonge, Anns. Pharm., France, January 1950, pp. 46-61.

Murat: Etudes pharmacodynamiques de la polyvinylpyrrolidone, Prod. Pharma. September 1949, pp. 397-403.

Claims (1)

1. AN AQUEOUS VEHICLE FOR INSOLUBLE MEDICINAL AGENTS COMPRISING ABOUT 0.1 TO ABOUT ONE PERCENT OF A LOW VISCOSITY ALKALINE SALT OF CARBOXYMETHYLCELLULOSE AND ABOUT 0.1 TO ABOUT THREE PERCENT OF A HYDROPHILIC POLYVINYL COMPOUND SELECTED FROM THE GROUP CONSISTING OF POLYVINYL PYRROLIDONE AND POLYVINYL ALCOHOL.