US3926817A

US3926817A - Glidants and process for preparing the same

Info

Publication number: US3926817A
Application number: US492786A
Authority: US
Inventors: Eiichi Nakajima; Tadashi Morioka; Kozo Kurihara; Takashi Kobayashi
Original assignee: Sankyo Co Ltd
Current assignee: Sankyo Co Ltd
Priority date: 1970-03-27
Filing date: 1974-07-29
Publication date: 1975-12-16
Anticipated expiration: 1992-12-16
Also published as: DE2115116C3; DE2115116B2; FR2083622B1; DE2115116A1; FR2083622A1; CH562614A5; GB1296007A

Abstract

Improved glidants having excellent gliding properties, i.e., improving or eliminating those disadvantages encountered in the prior art, for example, capping of the finished pharmaceutical preparations, delayed disintegration of the finished pharmaceutical preparations, lowering of the dissolution-out rate of the active ingredient and the like, which comprises certain known glidants wet-treated with a surface active agent, said known glidants being selected from higher fatty acids, the metal salts thereof and hydrogenated vegetable oils. The present glidants are prepared by subjecting the known glidants to wet treatment with a surface active agent.

Description

United States Patent Nakajima et al.

GLIDANTS AND PROCESS FOR PREPARING THE SAME Inventors; Eiichi Nakajima; Tadashi Morioka;

K020 Kurihara; Takashi Kobayashi, all of Tokyo, Japan Assignee: Sankyo Company Limited, Tokyo,

Japan Filed: July 29, 1974 Appl. No.: 492,786

Related US. Application Data Continuation of Ser. No. 336,372, Feb, 27, 1973, abandoned.

Foreign Application Priority Data Mar. 27, 1970 Japan 45-25756 US. Cl. 252/11; 252/33; 252/39; 252/52 A; 252/56 R; 252/565; 424/14; 424/22; 424/44 1m. C1 ClOM 1/40; ClOM 3/34; ClOM 5/16; ClOM 7/22 Field of Search 424/14, 22, 44; 252/11, 252/39, 33,56 R, 56 s, 52

[56] References Cited UNITED STATES PATENTS 3,5 l8.345 6/1970 Dines et al 252/11 3,518,346 6/l970 Cox 252/ll 3,719,599 3/1973 Gianbattista et al 252/11 Primary ExaminerDelbert E. Gantz Assistant E.\'aminerl. Vaughn Attorney, Agent, or FirmFlynn & Frishauf 57 ABSTRACT Improved glidants having excellent gliding properties, i.e., improving or eliminating those disadvantages encountered in the prior art, for example, capping of the finished pharmaceutical preparations, delayed disintegration of the finished pharmaceutical preparations, lowering of the dissolution-out rate of the active ingredient and the like, which comprises certain known glidants wet-treated with a surface active agent, said known glidants being selected from higher fatty acids, the metal salts thereof and hydrogenated vegetable oils. The present glidants are prepared by subjecting the known glidants to wet treatment with a surface active agent.

9 Claims, No Drawings GLIDANTS AND PROCESS FOR PREPARING THE SAME This is a continuation of application Ser. No. 336,372, filed Feb. 27, 1973, and now abandoned.

This invention relates to improved glidants and a process for preparing the same.

More particularly, it is concerned With improved glidants comprising a glidant substance wherein said glidant substance is subjected to wet treatment with a surface active agent, said glidant substance being selected from the group consisting of higher fatty acids. the metal salts thereof and hydrogenated vegetable oils and with a process for the preparation of such improved glidant.

It is wellknown in the art that a certain type of adjuvants or glidants which have been widely employed for the production of various pharmaceutical preparations, e.g.. powders, capsules, tablets and the like have troublesome disadvantages that they show such undesirable characteristics as poor disintegration of the finished pharmaceutical preparation, prolonged dissolutionout rate of the active ingredient, especially they have a pronounced tendency to cause capping when used in making tablets. In some cases, other types of glidants such as boric acid, sodium benzoate, sodium chloride, leucine. Carbowax (Registered Trade Mark), sodium stearate and the like have been also utilized in the pharmaceutical preparations, especially those required for hydrophilic property, e.g., water-soluble tablets, but these glidant substances were known to exert a poor glidant effect as well as toxicity and hygroscopicity so that they were kept away from general utilizability.

As a result of our extensive studies to develop a new and improved glidant having no disadvantages as seen in the prior art glidants, it has been unexpectedly found that a certain type of the known glidant substances, i.e., those selected from the group consisting of higher fatty acids, the metal salts thereof and hydrogenated vegetable oils exhibit a highly excellent glidant effect when they are subjected to wet treatment with a surface active agent.

The above finding is quite surprising because it has been generally understood in the art that a glidant exhibits its glidant effect due to its surface properties and thus, when treated with a substance having no gliding property per se, such a glidant should lose its inherent glidant property.

However, in contrary to the above-depicted prejudice, the improved glidant of this invention can hold inherent glidant effects such as the improvement in fluidity, the lowering of the excluding force from punches upon making tablets, the increase in bulk density, the prevention of anchoring and the like and simultaneously perform almost complete elimination of the disadvantages accompanied with the prior art glidants. e.g., poor disintegration, lower dissolution-out rate and the like, as compared with the prior art glidants. Still more surprisingly, in the case of making tablets the improved glidant of this invention can effectively prevent the low tablet hardness and the development of capping, which are believed inherent in the prior art glidant.

It is, therefore, a primary object of this invention to provide an improved glidant which shows highly excellent glidant ability without the disadvantages inherent in the prior art, expecially capping, delayed disintegration and low dissolution-out rate. 1

It is another object of this invention to provide a process 'forthe preparation of an improved glidant having desirable characteristics.

These objects and the advantages of this invention will be apparent to those skilled in the art from the detailed description below.

The glidant of this invention, as explained above. has an essential feature that it comprises a glidant substance known per se, said substance being selected from the group consisting of higher fatty acids, the metal salts thereof and hydrogenated vegetable oils, which substance is subjected to wet treatment (or treat ment under a wetting condition) with a surface active agent. I

The term wet treatment" as used herein is contemplated to include kneading procedure and other procedures commonly employed for absorption between solid phase and liquid phase.

In another aspect of this invention, the process of this invention comprises subjecting the selected glidant substance to wet treatment with a surface active agent.

In effecting the process of this invention, the preferred embodiment can be carried out according to the flow sheet as illustrated below.

. Drying Surface I Solvent Dissolution o Glidant of Lhisl invention In the abovementioned embodiment, the wet treatment may be effected as set forth above. The drying may be suitably effected by a conventional drying procedure, e.g. hot air drying, aeration drying, vacuum drying and the like. The pulverization may be suitably effected by means of a conventional grinder, e.g.. impact grinder, pneumatic grinder and the like. It is desirable that the particle size of the ground glidant be in the range of 10 ,u or less, but larger particle size may also be favourably employed. Examples of the glidant substances to be treated according to the process of this invention include stearic acid, magnesium stearate, calcium stearate and hydrogenated castor oil [e.g. Lubriwax (trade name, available from F reund Industrial Company, Japan) and Sterotex (trade name, available from Capital City Products Company, U.S.A)]. If desired, any combination of the above-illustrated glidant substances may also be employed in this invention. The surface active agents which may be employed in this invention may be of any type of non-ionic, anionic and cationic type surface active agents. Of these surface active agents are preferable polyoxyethylenepolyoxypropylene block polymers, e.g., those having the structure Hon? H OJ1(C;,H.,O)b(C -H O)CH wherein either the sum ofa and c is 30 35 and b is 25 30 or the sum ofa and cis -150 and b is 25 30 and a molecularweight of either ca. 3000 or ca. 8,000. respectively [e.g. Pluronic F-68" and Pluronic L'64 (trade names. available from Asahi Denka Kogyo K.K.. Japan or from Wyandotte Chemical Co.. USA. )1. polyoxyethylene sorbitan fatty acid esters. e.g.. polyoxyethylene monostearate. monolaurate. monopalmitate. monooleate and trioleate; alkyl sulfate salts. e.g.. sodium lauryl sulfate: and the like. The amount of the surface active agent to be employed is not critical. but it is usual and effective to employ the surfactant at 20 7c by weight or less. preferably at 4 '7( by weight. based upon the total weight of the untreated glidant substance. The solvent which may be employed in the above wet treatment may be any of those that could dissolve the surfactant and not the untreated glidant substance. Examples of the solvents which may be employed include water. methanol. ethanol. acetone. chloroform and the like.

The following Examples are given for the purpose of illustrating of the advantages and embodiments of this invention. but they should not be construed to be limiting the scope of this invention. All parts and percentages are given by weight.

Table l Surface active agent Solvent Ptnl ox eth lene sorhitan A (Ethanol) monolaurate Polyoxyeth lene sorbitan B (Ethanol) tristearate Sorhitan monolaurate C (Ethanol) Sorhitan monooleate D (Ethanol) Pluronic L-fi4 E (Water) Pluronic F-os F (Water) Sodium lauryl sulfate G (Water) *Extruding force from the cylinder upon the pressure-molded product (Kg/cm) *Angle of repose of the powder llowctl out of the funnel.

EXAMPLE 1 The surface active agents indicated in the Table I below were respectively dissolved in the solvents indicated in the Table I to form the 5 7c solutions thereof.

It will be seen from the above Table II that the glidants of this invention exhibit excellent properties.

EXAMPLE 2 The molded products from the formulations indicated in the following Table [II and the No. 1 capsules filled with the same formulations were tested for their physical properties as below with the results which are summarized in the Table IV below.

Table III Sample No.

Chloramphenicol parts) I00 I00 I00 I00 100 I00 Lactose (parts) 40 39.? 39.3 39.3 37.2 37.2 37.2 Untreated StMg (parts) 0.7 2 .66 Sodium lauryl sulfate (powder. less than l(),u. parts) 0.7 0.]4 StMg treated with sodium lauryl sulfate (less than 0.7 2.8

l() u. parts) Total (parts) l40 I40 l40 I40 l-10 I40 [00 parts of StMg as subjected to wet treatment with an 5; aqueous solution ofsodium laur \l sulfate. dried and then pul\ erized.

Table IV Compound No. l 2 3 4 5 (1 7 Specific extruding force (kg/cm) L50 1.05 0.48 0449 0.50

Table IV-continued Compound No. l 2 3 4 5 o 7 Disintegration time of capsulelmin) X 8 I I 8 8 25 IS It will be seen from the above Table IV that the incor- Table VII poration of the surfactant alone does not provide so much appreciable glidant effect (Sample No. 2). the Sump H H H incorporation of the StMg alone provides a good glidant effect but poor disintegration ability (Sample Nos. Lactose gmnules (PMS) 3 I d 6 d th f l Untreated StMglparts) In an an e incorporation o asimp e mixture of StMg treated with sodium the surfactant and the StMg gives an insufficient period lauryl u (P l of disintegration time (Sample No. 7), whereas the Tom] (pans, 3015 glidants treated with the surfactant solution according x I r v g to this invention exert the desired effect (Sample Nos. The Mme m the 4 and 5 EXAMPLE 3 Five hundred mg. of the granule sample as obtained The powdery formulations shown in the following above was molded under pressure of 1 ton by means of Table V were formed by utilizing the treated StMg a conventional compression tester equipped with flat prepared in the above Example I and filled into No. 0 punches of l 1 mm. diameter. whereupon the excluding capsules. which were then subjected to a dissolutionforce from the punch was determined with a load cell. out test. The results are summarized in the following Table The results are summarized in the Table VI below. VIII.

Table V Sample No.

9 It) 11 I2 Chloramphenicol (parts) 500 SUI) 500 500 500 Lactose (parts) I50 I20 I 20 I20 I20 Untreated StMg (partsl 3U (B)* (parts) 30 (F)* (parts) 3U (6)" (parts) 30 Total (parts) 650 650 650 650 650 The same as in the ahou: Table I.

Table VI Table VIII l Excluding force Amount of the active ingredient eluted ('7?) 40 Sample No {mm [hc punch g Dissolution-out time l0 min. 20 min. 30 min Sample No. 15 92 a 81 95 98 9 5 14 23 ll) I5 76 5 II It) 45 78 It Wlll be seen from the above Table ,VIII that the 3 99 formulation containing the StMg treated with the surfactant (Sample No. 14) has a reducing action against the force excluding the tablets from the punch. i.e.. a glidant action as the formulation containing the un- It will be seen from the above Table VI that. when treated StMg (Sample No. 13) has.

I u f he lidan is formulated, the such a arge amo nt 0 t g t EXAMPLE 5 formulation contalning the conventional or untreated StMg (Sample No. 9) shows much lower dissolution- The powdery formulations were prepared having the out rate as compared with that containing no glidant formulas as indicated in the following Table IX. (Sample No. 8), whereas the formulations containing Table IX the StMg treated according to this invention (Sample Nos. 10. l l and I2) undergo little influence with such Sample l 6 17 lg factors and show a good dissolution-out rate.

Ground sugar (parts) I070 I058 U158 Methyl cellulose (50 opts ll) l0 l0 parts) EXAMPLE 4 Talc (parts) I20 1:11

L'ntreated Luhriwax (parts) l2 An appropriate amount of lactose was granulated Luhriwax treated with sorhitan monolaurate" 12 with a 4 7c starch paste and then dried. To the so obtained granules was incorporated the glidant indicated (,5 T l (puns) I2 I2 0 in the following Table VII. The resulting granules were molded and tested as follows.

50 parts of an lll'll elhnnulic solution of sorhitzin mnnnluurute was mixed and kneaded with low parts of Luhriuax. dried in vacuum and then puherired.

One thousand and two hundred mg. of the sample as obtained above was molded under pressure of 3.3 tons by means of a conventional compression tester equipped with flat punches of 16 mm. diameter. whereupon the excluding force from the punch was determined with a load cell.

Table X Sample No. Excluding force from the punch lkg.)

It will be seen from the above Table X that the formulation containing the Lubriwax treated with sorbitan monolaurate (Sample No. 18) exhibits a superior glidant power to that of the formulation containing the untreated Lubriwax (Sample No. l7).

EXAMPLE 6 The granules were prepared by incorporating a 4 starch paste to an appropriate amount of lactose and then granulating. The so otained granules were punched to the tablets having an uniform tablet height according to the formulae indicated in the Table Xl below.

*The same as in the above Example 2. Prepared b the same procedure as that of the just abme l.

The test results of the tablets thus prepared are summarized in the following Table Xll.

7 Table xn Sample No.

Strength of tablet (kg.) 3.2 5.5 5.2 Capping number* 12/20 0/20, 0/20 Disintegration time (min.) l l 14 *WehstenAhhe abrasion tester. in 2 minutes.

It will be seen from the above Table XlI that the tablets containing the glidants treated with a surfactant (Sample Nos. 20 and 21 have no capping. a high strength and a satisfactory disintegration time.

What is claimed is:

1. A glidant comprising a major amount of a glidant substance selected from the group consisting of a higher fatty acid. a calcium salt thereof, a magnesium salt thereof. and a solid hydrogenated vegetable oil. treated with a solvent solution containing a surface active agent in an amount sufficient to improve dissolution of the glidant substance. said solvent being a solvent for said surface activeagent and a non-solvent for said glidant substance. followed by drying and pulveri- Zation.

2. The glidant according to claim 1 wherein said glidant substance is stearic acid, magnesium stearate. calcium stearate or hydrogenated castor oil.

3. The glidant according to claim 1 wherein said surface active agent is a non-ionic. anionic or cationic surface active agent.

4. The glidant according to claim 1 wherein said surface active agent is a polyoxyethylene-polyoxypropylene block polymer. a polyoxyethylene sorbitan fatty acid ester or an alkyl sulfate salt.

5. The glidant according to claim 1 wherein said surface active agent is a polyoxyethylene-polyoxypropylene block polymer having the structure wherein either the sum of a and c is 30 35 35 and b is 25 30 or the sum ofa and c is and b is 25 30 and having a molecular weight of either about 3,000 or about 8.000; a polyoxyethylene sorbitan monoor tri-fatty acid ester having 12 18 carbon atoms in the fatty acid moiety; or sodium lauryl sulfate.

6. The glidant according to claim 1 wherein said surface active agent is employed in an amount of up to 20% by weight, based upon the total weight of said glidant substance.

7. The glidant according to claim 1 wherein said glidant substance is magnesium stearate and said surface active agent is sodium lauryl sulfate.

8. The glidant according to claim 1 wherein said glidant substance is magnesium stearate and said surface active agent is a polyoxyethylene-polyoxypropylene block polymer having the structure HO(C- -H O)a(CxH.;O)h(C H O)cH wherein either the sum ofa and c is 30 35 and b is 25 30 or the sum ofa and c is 140 150 and b is 25 30 and having a molecular weight of either about 3.000 or about 8.000.

9. The glidant according to claim 1 wherein the solvent is water methanol. ethanol. acetone or chloro-

Claims

1. A GLIDANT COMPRISING A MAJOR AMOUNT OF A GLIDANT SUBSTANCE SELECTED FROM THE GROUP CONSISTING OF A HIGHER FATTY ACID, A CALCIUM SALT THEREOF, A MAGNESIUM SALT THEREOF, AND A SOLID HYDROGENATED BEGETABLE OIL, TREATED WITH A SOLVENT SOLUTION CONTAINING A SURFACE ACTIVE AGENT IN AN AMOUNT SUFFICIENT TO IMPROVE DISSOLUTION OF THE GLIDANT SUBSTANCE, SAID SOLVENT BEING A SOLVENT FOR SAID SURFACE ACTIVE AGENT AND A NON-SOLVENT FOR SAID GLIDANT SUBSTANCE, FOLLOWED BY DRYING AND PULVERIZATION.

2. The glidant according to claim 1 wherein sAid glidant substance is stearic acid, magnesium stearate, calcium stearate or hydrogenated castor oil.

3. The glidant according to claim 1 wherein said surface active agent is a non-ionic, anionic or cationic surface active agent.

4. The glidant according to claim 1 wherein said surface active agent is a polyoxyethylene-polyoxypropylene block polymer, a polyoxyethylene sorbitan fatty acid ester or an alkyl sulfate salt.

5. The glidant according to claim 1 wherein said surface active agent is a polyoxyethylene-polyoxypropylene block polymer having the structure HO(C2H4O)a(C3H6O)b(C2H4O)cH wherein either the sum of a and c is 30 - 35 35 and b is 25 -30 or the sum of a and c is 140 - 150 and b is 25 - 30 and having a molecular weight of either about 3,000 or about 8,000; a polyoxyethylene sorbitan mono- or tri-fatty acid ester having 12 - 18 carbon atoms in the fatty acid moiety; or sodium lauryl sulfate.

8. The glidant according to claim 1 wherein said glidant substance is magnesium stearate and said surface active agent is a polyoxyethylene-polyoxypropylene block polymer having the structure HO(C2H4O)a(C3H6O)b(C2H4O)cH wherein either the sum of a and c is 30 - 35 and b is 25 - 30 or the sum of a and c is 140 - 150 and b is 25 - 30 and having a molecular weight of either about 3,000 or about 8,000.

9. The glidant according to claim 1 wherein the solvent is water methanol, ethanol, acetone or chloroform.