US 2538127 A
Description (OCR text may contain errors)
Patented Jan. 16, 1951 MEDICATED SUPPOSITORIES AND BASES THEREFOR Francis Saunders',pSkokie, and Albert L. Ray mond, Northfield, Ill., assignors to G. D. Searle & (30., Skokie, 111., a corporation of Illinois No Drawing.
.This invention relates to medicated suppositories which are stable under high-temperature storage and shipping conditions and yet which are readily disintegrated upon administration. In particular this invention relates to medicated suppositories having bases which are composed of arelatively high-melting, water-soluble or dis.- persible wax and a wax which melts substantially Application February 26, 1948, Serial No. 11,334
13 Claims. (01.167--6 i)f We have found that by using a base which combines the principle of disintegration by moisture at body temperature, but does not soften appreciably below its melting temperature, and is substantially insoluble inthe relatively high-melting, water-soluble wax. This invention further relates to suppository bases of the foregoing type.
.The desirability of administering drugs rectally has long been felt in the medical arts. As one means of accomplishing this, medicated SLIDDOSi-r tories have frequently. been used, though no completely satisfactory product for this purpose has yet-been devised.- Most medicated suppositories have been prepared by. incorporating the thera-, peutic agent in a base which-will melt at substantially body temperature, thereby releasing the. medicament. Such suppositories have the obvi-.
ous disadvantage of melting during storage in warm places where the temperatureapproaches body temperature, resulting in frequent economic. loss, -'or in-the' demand for refrigerated storage, which is at best inconvenient. Other supposi tories have been made with a base of such nature.
(as-for instance a so-called water-soluble wax) that they are relatively unaffected by temperature changes, but will disintegrate and release their medicament in the presence of moisture. While sucha product might appear to be an acceptable answer to the'difiiculties of rectal administration, in actual fact the rectum is a relatively dry cavity. One of the functions of the lining of the lower part of the large intestine is to absorb water from its-contents rather than to secrete it, so that there is actually little moisture-present just above the sphincter to bring about the disintegrationrof such a suppository. While such disintegration might in time occur even in the presence of very limited amounts Of moisture, we have found by actual trial on human subjects that such suppositories are in fact undesirable. .Among the reasons for this conclusion is the fact that, long before any such slow disintegration can occur, the presence 'ofthe solid mass above the sphincter causes a powerful expulsion reflex and the entire medication is lost. It is theobject of this invention, therefore, to provide a suppository which can be stored without deterioration under such conditions as are normally encountered, and which when used will disintegrate and liberate its medi-- cation without undue delay ordiscomfort.
with that of disintegration by heat, a suppository can be made which more nearly approaches-the desirable characteristics of effective clinical use and reasonable resistance to storage :in warm places. For, by choosing a water-soluble or Water-dispersible wax whose melting point is appreciably above such temperature as might -be encountered during normal storage, a marked a degree of resistance to such temperatures is im-,
. or even losing its shape.
parted to the mass. By combining with such a substance a waxy ingredient which (1) has a sharp melting point at aboutbody temperature, (2) is relatively hard and does not markedly soften below its melting temperature, and (3) is. substantially insoluble in the high-melting watersoluble wax, a base is obtained which is firm at room temperature andbecomes appreciably soft; at body temperature without completely melting. Thus itwill stand stor-;
age indefinitely under any temperature normally encountered, but is able to release its medicament readily under the gentle warmth and. peristaltic action of the intestine in" the presence of the relatively small amount of moisture occurring there-1.
in. By formulating the entire suppository somatthe amount of powdered drug (or of inert'pow-I dered diluent which may be used with the drug). is relatively large compared to the base, furtherstability .of the entire mass under warm storage conditions is assured, together with an increasedv tendency to disintegrate when used.
. In formulating such bases, we have found the following combinations of commercially available. waxes to be satisfactory components. The high-1 melting water-soluble wax is given first. These examples are representative of the waxes within the scope of the invention. It will be apparent to those skilled in the art that other equivalent materials can be used without departing from the spirit or scope of this disclosure. I A. Polyethylene glycol (molecular weight about 4000, meltingpoint 50-55 centigrade) and propylene glycol monostearate (M. P. 36-3'7 C.)
B. Polyethylene glycol (molecular weight about 6000, M. P. 58- 62 C.) and partially hydrogenated cottonseed oil (M. P. 36-38 0.).
C. Polyethylene glycol and glycerol monooleate (M. P. 38 (3.). The melting point of the.
glycerol mono-oleate depends upon its source and;
purity. The oily commercial products are unsatisfactory for our suppositories. Suitable solid esters melting in the range of 35 to 38 C. can beobtained from purified materials. See Krafit;
Berichte, 36, 4343 (1903) D. Polyethylene glycol andv cocoa butter (M. P. 30--34= 0.).
E. Polyethylene glycol and a paraflin fraction melting at 3638 C. and being in the main composed of eicosane.
F. Isosorbide monostearate (M. P. 54-58 C.) and propylene glycol monostearate.
G. Sorbitan monostearate (M. P. 47.5-50.5 C.)
and propylene glycol monostearate.
H. Isosorbide monostearate and a paraffin wax melting at 36-38 C. and being in the main composed of eicosane.
I. Isosorbide monostearate and cocoa butter.
J. Polyethylene glycol of molecular weight about 4000 withisosorbide monostearate mixed with propylene glycol monostearate.
K. Polyethylene glycol of molecular weight about 6000 mixed with propylene glycol monostearate and glycerol monolaurate (M. P. 28-30 C.).
L. Polyethylene glycol (M. P. 58-62" C.) and anhydrous lanolin U. S. P.
v M. Polyethylene glycol and a mixture (M. P. 36 C.) of 7 parts of cocoa butter with 1 part of spermaceti.
It is apparent from the foregoing examples that more than two waxes may also be used in formulating the bases to which this invention relates. For example, two or more high-melting, mutually-miscible, water-soluble bases may be mixed with an immiscible, lower-melting wax, or a high-melting wax may be mixed with two or more waxes which melt near body temperature and which are immiscible in the high-melting wax while miscible with each other.
HOCH2 CHzOCI-Iz) n-CH2OH in which the value of n is so chosen that the compound is a hard waxy material at room temperature, but melts at 50 to 55 C. Commercially available materials are generally a mixture of homologues; in the mixture preferred by us, the. average value of n is about 90. A somewhat harder polyethylene glycol wherein n averages about 135 is also quite satisfactory. While such waxes are completely soluble in water, when formed into a hard suppository they resist the action of the relatively small amount of moisture in the rectum almost indefinitely, and thus are completely useless as suppository bases. As the second ingredient of our base, we prefer to use a fatty acid ester of propylene glycol whose melting point lies between 35 and 37 C. Such esters are not soluble in water. The exact fatty acid mixture used to form the ester is not of critical importance; several such esters are commercially available with appropriate melting points, among which we have found propylene glycol monostearate to be quite satisfactory. Since the fatty acid esters are not miscible with the polyoxyethylene glycol described above, the base is made homogeneous only by vigorous stirring while cooling. As a further result of this immiscibility, when the fatty ester of propylene glycol melts, it does not affect the polyoxyethylene glycol which remains in solid condition.
We have found that higher fatty acid esters of the hexitols obtained by reduction of hexoses are also satisfactory as the relatively high-melting, water dispersible wax. These hexitols exist as mixtures of the open-chain form with anhydrides formed by the elimination of one or two moles of water. Their esters with fatty acids are either waxy solids or viscous oils, and are all water-dispersible at body temperature. sorbitan monostearate (prepared from sorbitan by esterification with stearic acid) and isosorbide monostearate (prepared similarly from isosorbide) have been found to be particularly adapted to our novel suppository bases.
The melting point of the relatively high-melting wax should be above the highest temperature to be expected in storing and shipping the suppositories. In general the range should start at about Fahrenheit and 44 centigrade. The upper limit of the melting point should be chosen with regard to the hardness of the waxes and the problem of compounding and pressing or casting the suppositories. The melting point should not be so high that in mixing the melted ingredients the medicament is partly destroyed due to thermal instability. In practice the upper temperature need not exceed F. or 60 C., and for most purposes should not exceed 167 F. or 75 C. Thepreferred range is about 122-131" F. or 50-55 C. Seldom are temperatures above this range met in shipping or in storage, and the waxes are sufficiently low-melting to afford easy compounding and pressing or casting of the suppositories.
The melting point of the low-melting wax should be substantially that of body temperature, which is 37 C. In actual practice it has been found that the melting point can range from about 30 C. to about 38 C. The preferred melting range is from 35-38 C. In practice it is difficult to obtain accurate melting points of substances melting in the range of 30-38 C. Generally the solidification point is the one actually determined. It is usually observed that the solidification point of a given substance is a few degrees lower than the melting point of the substance, due undoubtedly to superheating during the melting point determination. For example, the solidification points of samples of propylene glycol monostearate, which have melting points in the range of 35-37 C., are generally in the range of 3335 C. Similarly, the polyethylene glycol of melting point 50 55 C. commonly has solidification points in the range of 4'7--52- C.
In order that the finished suppository be stable inwarm climates it is important that the quantity of this low-melting ingredient in the base be small enough so that when it has melted, the finished suppositor will not lose its shape, but there must at the same time be suficient present so that when it does melt after being used, the finished suppository is softened sufficiently that disintegration may start. We have found that a proportion of 20 to 80% by weight in the base of the wax which melts substantially at body temperature is satisfactory and desirable in preparing a suppository according to this invention. With fatty esters of propylene glycol and polyethylene glycols, it has been found that 20 to 60% by weight of the lower melting wax is preferred.
We have found that the ratio of drug (including inert powdered diluent thereof) to base is also important in formulating a suppository which wi11 achieve the object of this invention. The upper limit is determined by the readiness with which the mass can be mixed and shaped, either by casting, molding, compression or otherwise. Since the presence of powdered drug or diluent aids disintegration of the suppository, the lower thatabout 35 to 70% by weight of powdered drug and/or diluent are the preferred proportions. It is generally desirable'thatthe'powdered diluent be mainly water-soluble, in order that it may be absorbed with the drug and thus removed. It is not necessary that all the diluent be water-soluble since starch and gelatin, which are only partly soluble, are quite satisfactory as part of the inert powder. These materials swell with'wa'ter and are useful in aiding the disintegration of the suppository.
'While our suppository bases as herein disclosed are made up of a relatively high-melting watersoluble wax or mixture of such waxes and a wax or mixture of waxes melting at substantially body temperature and substantiall insoluble in the higher-melting wax or waxes, other components may be incorporated into our bases. Among such components are lubricants like castile ,or soft soap, gelatine, oleic acid, stearic acid and glycerol. For ease of removal from molds, substances such as lycopodiurn powder or talc may be used. Coatings of gelatine or flexible collodion may be applied. It is to be understood that such additions or modifications are not outside the scope of this invention. Other additives will be apparent to those skilled in the art without departing from the spirit or scope of our disclosure and claims.
This application is a continuation-in-part of our prior, copending application Serial No. 605,836, filed July 18, 1945, now abandoned.
Our invention is further disclosed by the following examples, which are illustrative onl and in no way limit the scope of our invention. The relative amounts are given in parts by weight.
Example 1 As 'an example o'f'a suppository which has the properties desired to be furnished by this 'in-'- vention, the following composition may be used:
Parts Aminophyllin (finely powdered) 50 Polyoxyethylene glycol (M. P. EEO-55 C.) 25 Propylene glycol fatty acid ester (M. P.
dose, is desired, the following illustrates the use of a diluent:
, Parts Aminophyllin (finely powdered), 25 Sodium chloride (finely powdered) 25 Polyoxyethylene glycol (M. F. 50-55 C.) 25
Propylene glycol fatty acid ester (M. 'P.
The glycol and ester are melted together, and the aminophyllin and sodium chlorid added and the whole stirred vigorously during cooling. A'2 gm.
suppository willcontain 500 mg. of aminophyllin, 7 Starch l '-40 or a 1 gm. suppository will have a dose of 250 mg. of thedrug. The diluent used in this example may be replaced by other suitable 'diluents, certain of which are mentioned in the other examples.
Example 3 Similarly suppositories may be made 'using drugs requiringmuch smaller doses by increasing the diluent used:
. Parts Phenobarbital 3 Dextrose 33 Polyoxyethylene glycol (M. P. 50-55" C.) 32
Propylene glycol fatty acid ester (M. P."
When made into 1 gmysuppositories, each will contain a dose of 30 mg. of phenobarbital.
Example 4 Parts Morphine"sulfate 0.266 Sodium sulfate '60 Polyoxyethylene glycol (M. P. 50-55 C.) v20 Propylene glycol fatty acid ester (M. P. 35-3'l C.) 20' Example 5 According to the method of Example 1, a suppository is made of the following components:
The resulting composition is easily pressed, does not stick to the die and is firm and stable at temperatures up to 56 C.
Example 6 A Suppository is made of the following composition:
Parts Sorbitan monostearate Cocoa butter 20 Aminophyllin 50 Sucrose 0 Starch .4 40
The product is firm and. not sticky.
Example 7 A satisfactory suppository is compounded of the following ingredients accordingto themethodv of Example 1:
Example 8 A satisfactory suppository has the following. formula:
Parts Polyethylene glycol (M. P. 50-55 C.) u 28 Propylene glycol monostearate 42 Aminophyllin 50 Sucrose '40 7. Example 9 A satisfactory suppository is compounded as follows:
Parts Polyethylene glycol (M. P. 58-62 C.) 4O Propylene glycol monostearate Glycerol monolaurate Powdered medicament and diluent 130 Example 10 The following formulation gives an excellent suppository having all the desired properties of firmness, heat resistance and ease of compounding:
Parts Polyethylene glycol (M. P. 50-55 C.) Propylene glycol monostearate; Isosorbide monostearate 50. Aminophyllin 50 Sucrose 10 Starch Example 11 A suppository is made according to the following formulation.
Parts Aminophyllin powder 2, 80 Potato starch 2,038 Powdered sugar 2,038 Sodium pentobarbital 569 Polyethylene glycol of M. P. -55 C 812 Propylene glycol monostearate 1,232
Example 12 A suppository made according to the following formula is stable and easily compounded and pressed:
Example 13 A satisfactory suppository can be made according to the following formula:
Parts Aminophyllin powder -o 25 Sodium 5-allyl-5-( l-methylbutyl) barbiturate 5 Starch 0 Sugar, powdered 20 Polyethylene glycol of M. P. 50-55" C 3 Propylene glycol monostearate 27 Example 1 4 The following formula gives a satisfactory suppository:
Parts Aminophyllin powder 5 Sodium phenobarbital 5 Starch 20 Sugar, powdered 0 Polyethylene glycol of M. P. 50-55 C 27 Propylene glycol monostearate 3 8 Example 15 v A stable suppository can be formulated as fol lows: Parts Aminophyllin powder 500 Sodium pentobarbital 100 Starch 500 Powdered sucrose 500 Polyethylene glycol of M. P. 50-55" C 20o Propylene glycol monostearate 200 Example 16 A cast suppository can be produced in accordance with the following formula:
. Parts Aminophyllin powder 40 Polyethylene glycol of M. P. 50-55" C Propylene glycol monostearate 80 In practice it is advisable to use heated dies with: this formulation.
Example 17 A medicated suppository can be made accord-Z ing to the following formula:
Parts Tannic acid 20 Iodoform 20 Cocoa butter 80 Polyethylene glycol of M. P. 58-62 C 80 The iodoform is dissolved in the melted cocoa butter and the tannic acid and polyethylene gly col are thoroughly mixed with the melt. The"- warm mixture is then cast into Z-gram suppositories. I 1
Example 18 A medicated suppository compounded according to the following formula is stable and satisrnolds ;to form factory: V
' v I Parts Aminophyllin powder 250 Potato starch 275 Powdered sucrose 275 Sodium pentobarbital ,50 Polyethylene glycol of M. P. 50 -55 C ;;"'l5 Cocoa butter 75 We claim:
1. A medicated suppository comprising a base which consists of not less than 20% and not more than 60% by weight of a relatively high-melting, water-soluble polyethylene glycol wax, the bal-' ance of the base being a fatty acid ester of propylene glycol which melts substantially atbody temperature but does not soften appreciably below its melting temperature.
2. A medicated suppository in which the has consists of not less than 20% and not more than 60% by weight of a polyethylene glycol whose melting point lies between 50 and 55 0., the balance of the base being a fatty acid ester of propylene glycol whose melting point lies between 35 and 37 C., and which does not soften ap-. preciably below its melting temperature.
. 3. A medicated suppository in which the base consists of not less than 20% and not more than 60% by weight of a polyethylene glycol whose melting point lies between 50 and 55 C., the balance of the base being a fatty acid ester of pro-' pylene glycol and whose melting point lies between 35 and 37 0., and which does not soften appreciably below its melting temperature, and in which suppository the proportion of powdered drug, including inert diluents thereof, lies be tween 20 and 85% by weight of the total suppository.
4. A medicated suppository comprising a base which consists of not less than 20% and not more than 60% by weight of a polyethylene glycol whose melting point liesbetween 50 and 55 C. and whose average molecular weight is about 4000, the balance of the base being propylene glycol monostearate.
5. A medicated suppository comprises aminophyllin and a base which consists of not less than 20% and not more than 60% by weight of a polyethylene glycol whose melting point lies between 50 and 55 C. and whose average molecular weight is about 4000, the balance of the base being propylene glycol monostearate.
6. A medicated suppository comprising aminophyllin, a barbiturate and a base which consists of not less than 20% and not more than 60% by weight of a polyethylene glycol whose melting point lies between 50 and 55 C. and whose aver age molecular Weight is about 4000, the balance of the base being propylene glycol monostearate.
'7. A medicated suppository comprising aminophyllin, sodium pentobarbital and'a base which consists of not less than 20% and not more than 60% by weight of a polyethylene glycol whose melting point lies between 50 and 55 C. and whose average molecular weight is about 4000, the balance of the base being propylene glycol monostearate.
8. A suppository base comprising not less than 20% and not more than 60% by weight of a relatively high melting water soluble polyethylene glycol waX and a fatty acid ester of a polyhydric saturated aliphatic alcohol which melts sub stantially at body temperature, but does not soften appreciably below. its melting temperature.
9. A suppository base comprising not less than 20%-and not more than 60% by weight of a polyethylene glycol, the melting point of which is in the range of 50-55 centigrade, and a fatty acid ester of a polyhydric saturated aliphatic alcohol 10 which has a melting point in the range of 37 C. and which does not soften appreciably below its melting point.
10. A suppository base comprising not less than 20% and not more than 60% by weight of a polyethylene glycol, the melting point of which lies between -55 C. and which has an average molecular weight of about 4000, and propylene glycol monostearate.
. 11. A medicated suppository comprising a base as defined in claim 8 and 20-85% by weight of powdered drug and inert diluents.
12. A medicated suppository comprising a base I as defined in claim 9 and 20-85% by weight of powdered drug and inert diluents. I
13. A medicated suppository comprising a base as defined in claim 10 and 20-85% by weight of powdered drug and inert diluents.
FRANCIS J. SAUNDERS. ALBERT'L. RAYMOND.
REFERENCES CITED The following references are of record in the file of this patent:
UNITED STATES PATENTS Number Name Date 1,930,353 Kollek et al Oct. 17, 1933 2,055,063 Bird Sept. 22, 1936 2,149,005 Bockmuhl Feb. 28, 1939 2,241,331 Shelton May 6, 1941 OTHER REFERENCES Friesen, Pharmazie, vol. 1, pages 76-79, July