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Publication numberUS2861920 A
Publication typeGrant
Publication dateNov 25, 1958
Filing dateMay 4, 1954
Priority dateMay 4, 1954
Publication numberUS 2861920 A, US 2861920A, US-A-2861920, US2861920 A, US2861920A
InventorsDale Jack K, Ross Samuel L
Original AssigneeUpjohn Co
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Therapeutic suspensions of steroids containing pvp and/or pva
US 2861920 A
Abstract  available in
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Claims  available in
Description  (OCR text may contain errors)

United States Patent 2,8 1, 20 THERAPEUTIC SUSPENSIONS. 0F STEROIDS CONTAINING PVP AND/0R PVA Jack K. Dale, Kalamazoo, and Samuel 'L..Ross, Kalamazoo Township, Kalamazoo County, Mich., assignors' to The Upjohn Company, Kalamazoo, Mich., a corporation of Michigan 7 N0 Drawing. Application May 4, 1954 Serial No.42 7,678 9 Claims. (Cl. 167-65) This invention relates to new compositions of matter containing steroids and to a process for the preparation thereof. More particularly, it relates to compositions containing an insoluble steroid in combination with one or more hydrophilic polyvinyl compounds, said combinations being either in the form i suitable for therapeutic use or in the form of a dry admixture which is suitable forthe extemporarieous preparation of an aqueous fluid. The invention also relates to a process for inhibiting crystal growth of steroids.

The preparation of stable aqueous suspensions of insoluble steroids has presented considerable difficulties. For example, aqueous suspensions of crystalline cortisone acetate, progesterone, testosterone propionate, estradiol monobenzoate, and the like, are characterized by crystal growth. This is a real problem since large crystals can be a source of great irritation to patients, can cause mechanical difliculties in attempting to pass large crystals through fine hypodermic needles, and have a considerable effect upon the suspendability of the active material. So little is known about the mechanism of crystal growth, that it is almost impossible to predict what materials or methods will retard it.

It is an object of the invention to provide novel compositions of matter containing insoluble steroids which are suitable for therapeutic use. Another object of the invention is to provide stable aqueous suspensions of steroids suitable for therapeutic use which will remain relatively free of crystal growth, even after extended periods of time. Another object of the invention is to provide dry therapeutic compositions containing a steroid which will readily form a stable suspension on the addition of an aqueous vehicle without being subject to excessive crystal growth. Other objects are to provide novel procedures for preparing such compositions and novel ways of inhibiting the crystallization of steroids. Still other objects of the invention will be apparent to those skilled in the art to which this invention pertains.

The invention provides compositions of matter containing a hydrophilic polyvinyl compound such as polyvinyl pyrrolidone, polyvinyl alcohol, or the like, and mixtures thereof, in combination with a steroid such as cortisone acetate, progesterone, testosterone propionate, estradiol monobenzoate, or the like, said compositions being either in the form of an aqueous suspension or in the form of a dry admixture readily dispersible to form the same. These suspensions are characterized by the absence of excessive crystal growth.

The marked superiority of the hydrophilic polyvinyl compounds of the invention as crystal growth retardants for therapeutic steroid compositions as compared with other suspending agents is clearly evident from the data set forth in the following tables. Thus, steroid suspensions prepared according to the invention are characterized by the absence of undue crystal growth in suspension even after storage for extended periods of time at room temperature.

V The following tables compare the effect of two hyd r ophilic polyvinyl compounds with otherwsuspending agents on the; crystal growth of a steroid, illustrf ively, cortisone acetate arid cortisohe acetate hydrate, the com: parisons being made after storage at room temperature for the various times indicated. Table I illustrates the effect of the hydrophilic polyvinyl compounds on the crystal growth of cortisone acetate as compared with other suspending agents. I aqueous suspension in the concentration of fifteen milligrams per cubic centimeter with 0.1 percent weight by volume of the suspending agent.

TABLE 1 The effect of various sas'pen ding agents on the crystal 'growth of cortisone acetate in suspension Crystal Size suspending Agent Initial 4 days 3 wks. 2 mos.

Polyvinyl Alcohol. l 10 10 l0 Polyvinyl Pyrrolidone 10 10 10 Acacia U. S. P 10 10 Dextran 10 50% 10n Sodium Oarboxymethylcellulose- 10p. 20% 10IL TABLE II The efiect of various suspending agents on the crystal growth 09 cortisone acetate in aqueous suspension The data given in Table II shows that only polyvinyl alcohol and polyvinyl pyrrolidone of the suspending agents tested inhibit growth of cortisone acetate hydrate.

Table III illustrates various preservatives which can be substituted for Quatresin and the effect of the preservatives on the crystal growth of cortisone acetate hydrate in aqueous suspensions. No suspending agent was used.

TABLE III The efiect of various preservatives 0n the crystal growth of cortisone acetate in aqueous suspension 7 Crystal Size Preservative Initial 1 day 2 wks. 2 mos.

0.02% Quatres'in (my-ristyl gamma picollnium chloride) 10n 1% 10[L 1% 10;l: 100% 10u 0.01% Merthiolate" (sodium ethylmercurithloa 1 The cortisone acetate is in Ro-suspendlbility Crystal Growth Suspending Agent Initial, Initial 3 wks.

Shakes Polyvinyl Alcohol. 3-10 Polyvinyl Pyrrolidone. 3 Acacia U. S. P 3-10 Dextran 1-2 Sodium Oarboxymeth- 1-2 ylcellulose. Pectin N. F 1-2 Methylcellulose l-2 Sodium Alginatc 20%Z1Up 20% 10p. 100%, 20-00 20 (clumped) 20 (clumped) 1-2 ll-2 *No crystal growth after ten months.

Since the clumps obtained in the three instances noted above could not be broken up, suspensions of this type are unsatisfactory for ophthalmic use or injection and are generally unsuitable for therapeutic use because of lack of uniformity in dosage.

Of the suspending agents tested, only the aqueous suspensions of cortisone acetate hydrate containing polyvinyl alcohol and polyvinyl pyrrolidone were both readily resuspendible and free of crystal growth. These suspensions are therapeutically useful, especially for ophthalmic use or parenteral injection.

Table V illustrates the efiect of suspending agents set forth in Table I and Quatresin, on crystal growth in aqueous suspensions of cortisone acetate hydrate (at a concentration of fifteen rugs/cc.) after storage at room temperature for various periods of time and also the resuspendibility of these suspensions after an extended period of time. In all instances, 0.02 percent Quatresin and 0.1 percent suspending agent, weight by volume, are used.

4 tion are of pharmaceutical grade, non-toxic, inert and capable of being sterilized without change in composition. On the addition of water to a dry composition containing a steroid and the selected hydrophilic polyvinyl compound, followed by mixing, a stable steroid suspension is readily obtained.

The polyvinyl pyrrolidone used in the compositions described herein is sold by the General Aniline and Film Company under the trademark Plasdone and is characterized by a viscosity coefficient, i. e., K value, of 26 to 36 and a molecular weight of about 40,000. However, it is to be understood that the invention is not to be limited to the use of this specific polyvinyl pyrrolidone since other equivalent polyvinyl pyrrolidones 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 are also obtained by the use of a polyvinyl pyrrolidone outside of this molecular weight range.

The polyvinyl alcohol utilized in the compositions described herein is sold by the DuPont Company under the trademark ElvanoP 51-05 and is characterized by a viscosity of four to six centipoises (four percent aqueous solution at twenty degrees centigrade), a pH of six to eight and a 86 to 89 percent hydrolysis from polyvinyl acetate. It is to be understood, however, that the invention is not limited to the use of this specific polyvinyl alcohol since any other equivalent polyvinyl alcohol of pharmaceutical grade can likewise be used to achieve similar results.

The amount of hydrophilic polyvinyl compound which can be used in the compositions of the invention can vary from a range of 0.01 percent weight by volume up to ten percent weight by volume. However, the preferred range of concentration is between 0.1 to five percent weight by volume. The preferred range varies with the type of preparation however. For example, for an eye preparation, a concentration of about 0.1 to about 0.4 percent weight by volume is preferred. Higher concentrations make eyelids sticky. For injection use concentrations of one to two percent are preferred to keep the suspension from darkening.

The compositions of the present invention are especially suitable for therapeutic application either parenterally,

orally, or topically. For example, sterile aqueous suspensions of cortisone acetate, cortisone acetate hydrate, and the like, are especially useful as topical ophthalmic TABLE V Re-sus endibilit Or stal Growth Quatresin suspending p y y Agent Initial, Shakes 10 mos., Shakes Initial 3 wks.

Polyvinyl Alcohol 3-10 3-10 10 (10 3l0 3-10 10p. 1%Zl0p 10 (caked)..- 20 (eaked)..- 10p. 100%.20-80 Dextran 10 (caked). 20 (caked).-- 10 100%,1070n Sodium Garboxymethyleellulose. 20 (caked)..- l0 100%. 20-80 1. Pectin N. F 20 (caked)... 10 100%, 20-60 1 Methyleellulose 20 (caked).-. ]0,u 20%.10 Sodium Algmate 1 1-2 10 100%. 20-60;; ControI-only 0.02% Quatresin 1-2 10, 20% 10 In combination with Quatresln, only the aqueous susapplications. Ophthalmic preparations of this nature are pensions of cortisone acetate hydrate containing polyvinyl alcohol and polyvinyl pyrrolidone were readily re-suspendible and free of crystal growth.

The cortisone acetate hydrate used herein is conveniently prepared by dissolving cortisone acetate in a watermethanol mixture (e. g., 100 grams of cortison acetate is dissolved in a mixture of 250 milliliters of water and 25 liters of methanol), filtering the mixture to remove impurities, allowing the filtrate to crystallize and carefully drying the crystals to obtain cortisone acetate in its hydrated form.

The polyvinyl hydrophilic compounds of the. inven- Iacycline, tetracycline, polymyxin,

not perceptible in the eye and are non-irritating. For oral use, cortisone acetate, progesterone, and the like, are especially suitable.

Furthermore, other therapeutic materials can be incorporated with the compositions containing the selected hydrophilic polyvinyl compound and steroid to form new and extremely valuable compositions. Such therapeutic materials include antibiotics such as neomycin, penicillins such as penicillin G, penicillin O, procaine penicillin, and the like, bacitracin, chloramphenicol, streptomycin, dihydrostreptomycin, erythromycin, oxytetracycline, chlortetcirculin, endomycin,

and the like, or mixtures of these antibiotics. It should be noted that the importance ofcotnbinations of an; antibiotic the individual members of these combinations. For. example, while combinations of neomycin and cortisone acetate have been prepared in the form of ointments, creams, jellies, powders, and the like, suspensions of these materials are particularly valuable fortherapeutic use. such as, for example, topically, ophthalmic application, oral administration, aerosols for the relief of-respiratorycdif.- ficulties, and the like. The 9oz-halo derivatives of the indicated steroids can be substituted therefor inthe preparations shown and described. By the addition of the selected hydrophilic polyvinyl compound to an aqueous suspension of an antibiotic such as neomycin,- and a steroid such as cortisone acetate, and the like, the stability imparted to these compositions greatly enhances their value.

A typical composition of the invention in the form of an aqueous suspension is prepared by providing a vehicle usually containing a hydrophilic polyvinyl suspending agent, a preservative to insure a sterile product, a lubricant (where opthalmic use is contemplated), a buffer to maintain the pH of the suspension between 6.5 and 8.0 and an isotonic agent to adjust the osmotic pressure approximately equivalent to 0.9 percent saline. Conventional preservatives, buffers, isotonic agents, and lubricants (glycerol, sorbitol, and the like), can be used. Suitable preservatives include 0.01 percent Merthiolate, 0.5 percent chlorobutanol, 0.02 percent Quatresin and 0.1 percent methylparaben. Non-toxic wetting agents such as Tween-80 (polyoxyethylene sorbitan monooleate), Quatresin, and the like, are included in the suspensions because their characteristic wetting action on crystals aids re-suspension after storage. The vehicle passing through a Hormann filter. The sterilized vehicle is combined aseptically with the desired sterilized steroid, the resulting composition passed through a sterile colloid mill and then bottled and sealed. In preparing a suspensionof a steroid. such as progesterone, cortisone acetate, or the like, the steroid is micronized or otherwise prepared in the desired particle size, sterilized, for example, by exposure to ethylene oxide vapor, and then combined with a suitable vehicle to form a suspension. Particle size of the steroid is significant since coarse particles will not pass through a hypodermic needle and in the case of an ophthalmic preparation, may cause irritation of the eye. It has been. found. that. proper. particle size is achieved in an oral preparation when the majority of the particles of the composition are within the range of about five to eighty microns, and for parenteral orophthalmic use, preferably fifteen microns. or. less in size.

Thus, in the preparationof a typical composition of the invention, between 0.01 percent and ten percent of the selected hydrophilic been dried and sterilized is mixed with at least 0.02 percent of a sterilized and dried steroid which is subject to crystal growth. The composition can exist in the form of a dried admixture for the extemporaneous preparation of an aqueous fluid. In the dry form, the product is very stable and can be stored for relatively long periods of time. To use the dry composition, an indicated amount of sterile water, sterile saline solution and other ingredients novel to the composition of this type are added, followed by mixture or agitation.

The following examples are illustrative of the comthis invention together with the procedure thereof but are not to be construed in any way as limiting theinvention thereto.

polyvinyl compound which has use.

EXAM-PERI A vehicle containing the following ingredients:

Grams Polyvinyl pyrrolidone 50 d-Sorbitol-crystalline 25 Quatresin 0.2 Sodium citrate 1 Sodium chloride 4 N/ 10 NaOH solution in sufficient pH between 6.8 and 7.5, q. s. Deionized water, q. s. 1000'cc.

quantity to adjust A vehicle containing the following ingredients:

Polyvinyl pyrrolidone Sodium chloride 9 Quatresin N/lO NaOHto adjust pH between 7.0 Deionized water, q. s., 1000 cc.

is isotonic and can pass through a 26 (or finer) gauge There is no evidence of. growth in hypodermic needle. particle size in'this suspension even after storage for a 17 monthvperiod.

EXAMPLE 3 propionate, a sterile, stable: suspension of testosterone propionate is obtained which is suitable for therapeutic There is no evidence of growth in particle size in this suspension even after storage, for 17 months.

EXAMPLE 4 A vehicle containing the following ingredients:

Grams Polyvinyl pyrrolidone 1 Dextrose 25 Neomycin sulfate 6 Sodium citrate 4.5 Quatresin 0.2

Deionized water, q.s. 1000 cc. is mixed and fil-ter sterilized. The vehicle is then com- The mixture is mill, bottled and sealed.

is no evidence of growth in EXAMPLE A vehicle containing the following ingredients:

Grams Polyvinyl alcohol 4 Soluble saccharin 1 Sucrose 700 Benzoic acid 1 Methylparaben 1 Deionized water, q. s. 1000 cc.

I is mixed. To the resulting solution is added fifty grams of cocoa, five grams of micronized progesterone (particle size less than ten microns) and 0.1 cubic centimeter of imitation black walnut flavor. The product contains particles less than ten microns in size and is characterized by a pleasant chocolate-nut flavor making it especially suitable for oral use.

EXAMPLE 6 A vehicle containing the following ingredients:

Grams Polyvinyl pyrrolidone 20 Sodium chloride 9 Quatrcsin 0.2

N/lO NaOH to adjust-pH between 7.0 and 7.5, q. s. Deionized Water, q. s., 1000 cc.

is mixed and filter sterilized. The vehicle is then combined aseptically with 25 grams of cortisone acetate hydrate which has been sterilized and micronized to a particle size of less than ten microns. The mixture is passed through a sterile colloid mill, bottled and sealed. The sterile suspension thus obtained has a pH between 7 and 7.5, is isotonic and can pass through a 26 gauge (or finer) hypodermic needle.

EXAMPLE 7 Following the procedure described in Example 6 except for the substitution of cortisone acetate hydrate by hydrocortisone acetate, a sterile suspension of hydrocortisone acetate is obtained which is suitable for therapeutic use. There is no evidence of growth in particle size in this suspension even after storage for a prolonged period of time.

. EXAMPLE 8 A vehicle containing the following ingredients:

- Grams Polyvinyl pyrrolidone 1 d-Sorbitol-crystalline 25 Quatresin 0.2 Sodium citrate 1 Sodium chloride 4 N/lO NaOH solution 1n sufficient quantity to adjust pH between 6.8 and 7.5, q. s. Deionized water, q. s., 1000 cc.

is mixed and filter sterilized. The vehicle is then combined aseptically with 25 grams of estradiol monobenzoate which has been sterilized and micronized to a particle size of less than ten microns. The mixture is then passed through a sterile colloid mill, bottled and sealed. The final product is a sterile suspension with a pH be tween 6.8 and 7.5.

EXAMPLE 9 A vehicle containing the following ingredients:

Grams Polyvinyl alcohol 4 Soluble saccharin l Sucrose 700 Benzoic acid 1 Methylparaben l Deionized water, q. s., 1000 cc.

is mixed. To the resulting mixture is added fifty grams of cocoa, five grams of micronized cortisone acetate (particle size less than ten microns) and 0.1 cubic centimeter of imitation black walnut flavor. The product contains particles less than ten microns in size and is especially suitable for oral use.

EXAMPLE 10 A vehicle containing the following ingredients:

Grams Polyvinyl pyrrolidone l Dextrose 25 Neomycin sulfate 6 Sodium citrate 4.5 Quatresin 0.2

Deionized water, q. s 1000 cc.

is mixed and filter sterilized. The vehicle is then combined aseptically with 25 grams of estradiol monobenzoate which has been sterilized and micronized to a particle size of less than ten microns. The mixture is passed through a sterile colloid mill, bottled and sealed. The final product is a sterile suspension of a pH between 7 and 7.5. The product is useful for topical application. After storage for an extended period of time, the suspension is free of crystal growth.

The use of neomycin sulfate in this example is illustrative only since other neomycin derivatives can also be used such as, for example, neomycin base, neomycin hydrochloride, neomycin citrate, and the like, to achieve similar results.

Similarly, other antibiotics such as bacitracin, chloramphenicol, erythromycin, peni-cillins such as penicillin O, penicillin G, procaine penicillin, and the like, oxytetracycline, chlortetracycline, tetracycline, circulin, endomycin, streptomycin, dihydrostreptomycin, polymyxin, and the like, can also be used to form compositions, either in dry form or in suspension, suitable for therapeutic use.

EXAMPLE 11 A vehicle containing the following ingredients:

I Grams Polyvinyl pyrrolidone 25 Sodium citrate 1 Merthiolate 0.1 Quatresin 0.2 Chlorobutanol 5 Sodium chloride 9 Deionized water, q. s., 1000 cc.

is mixed and filter sterilized. The vehicle is then combined aseptically with 25 grams of cortisone acetate which has been sterilized and micronized to a particle size of less than ten microns. The mixture is passed through a sterile colloid mill, bottled and sealed. The final product is a sterile suspension of a pH between 7 and 7.5 and a freezing point depression of 0.66 degree Centigrade. Crystal growth is greatly retarded after storage for a prolonged period of time.

EXAMPLE 12 7 Following the procedure described in Example 11 except for the inclusion in the vehicle of six grams of neomycin sulfate, a sterile, stable suspension of neomycin- 9 and cortisone acetate suitable for therapeutic use is obtained.

EXAMPLE 13 The following ingredients:

Polyvinyl alcohol "mg" 25 Polyvinyl pyrrolidone mg 25 Crystalline d-sorbitol mg 250 Bacitracin units 1000 Quatresin mg 1 Cortisone acetate mg 75 are intimately combined in the form of a fine powder (or suitably milled together) and placed in a vial. On adding five cubic centimeters of water and shaking for fifteen to thirty seconds, a non-irritating suspension results which is suitable for use as a nosedrop preparation even after storage for prolonged periods of time.

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

We claim:

1. An aqueous therapeutic suspension comprising a water-insoluble steroid subject to crystal growth and from 0.01 to ten percent weight by volume of a member selected from the group consisting of polyvinyl pyrrolidone, polyvinyl alcohol, and a mixture thereof.

2. An aqueous therapeutic suspension comprising a water-insoluble steroid subject to crystal growth, an antibiotic, and from 0.01 to ten percent weight by volume of a member selected from the group consisting of polyvinyl pyrrolidone, polyvinyl alcohol, and a mixture thereof.

3. A dry therapeutic composition suitable for the extemporaneous preparation of an aqueous suspension comprising a water-insoluble steroid subject to crystal growth and from 0.01 to ten percent weight by volume of a member selected from the group consisting of polyvinyl pyrrolidone, polyvinyl alcohol, and a mixture thereof.

4. A dry therapeutic composition suitable for the extemporaneous preparation of an aqueous suspension comprising a water-insoluble steroid subject to crystal growth, an antibiotic, and from 0.01 to ten percent weight by volume of a member selected from the group consisting of polyvinyl pyrrolidone, ture thereof.

5. An aqueous therapeut c suspension comprising a steroid selected from the group consisting of cortisone acetate, hydrocortisone acetate, estradiol monobenzoate, testosterone propionate, and progesterone and from 0.01 to ten percent weight by volume of a member selected from the group consisting of polyvinyl pyrrolidone, polyvinyl alcohol, and a mixture thereof.

6. An aqueous therapeutic suspension comprising cortisone acetate and from 0.01 to ten percent weight by volume of a member selected from the group consisting of polyvinyl pyrrolidone, polyvinyl alcohol and mixtures thereof.

7. An aqueous therapeutic suspension comprising cortisone acetate hydrate and from 0.01 to ten percent weight by volume of a member selected from the group consisting of polyvinyl pyrrolidone, polyvinyl alcohol and mixtures thereof.

8. An aqueous therapeutic suspension comprising cortisone acetate, an antibiotic and from 0.01 to ten percent weight by volume of polyvinyl pyrrolidone.

9. An aqueous therapeutic suspension comprising cortisone acetate hydrate, neomycin sulfate, and from 0.01 to ten percent weight by volume of polyvinyl pyrrolidone.

polyvinyl alcohol, and a mix- References Cited in the file of this patent UNITED STATES PATENTS 2,156,233 Wright Apr. 25, 1939 2,394,628 Meyer Feb. 12, 1946 2,671,749 Schultz Mar. 9, 1954 2,671,750 Macek Mar. 9, 1954 2,793,156 Souler May 21, 1957 FOREIGN PATENTS 880,046 Germany .Tune 18, 1953 OTHER REFERENCES

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Classifications
U.S. Classification514/39, 552/503, 514/171, 514/772.5, 514/179
International ClassificationA61K47/32, A61K9/00
Cooperative ClassificationA61K9/0014, A61K47/32
European ClassificationA61K9/00M3, A61K47/32