US2115491A

US2115491A - Methods of preparing pharmaceutical products adapted for injection into the human body

Info

Publication number: US2115491A
Application number: US76701A
Authority: US
Inventors: Philip A Kober
Original assignee: GD Searle LLC
Current assignee: GD Searle LLC
Priority date: 1936-04-27
Filing date: 1936-04-27
Publication date: 1938-04-26
Anticipated expiration: 1955-04-26

Description

Patented Apr. 26, 1938 UNITED STATES METHODS OF PREPARING PHARMACEUTI- CAL PRODUCTS ADAPTED FOR INJECTION INTO THE HUMAN BODY Philip A. Kober, Evanston, 111., assignor to G. D.

Searle & 00., Chicago, Ill., a corporation or Illinois No Drawing. Application April 2'1, 1936, Serial No.- 76,701

12 Claims.

This invention relates to methods of preparing,

pharmaceutical products, and more particularly to processes for the production of medicinal agents in the nature of irritants adapted for introduction, as by injection, into various regions of the human body for the purpose of correcting structural abnormalities through the production of changes in the tissues involved or in contiguous tissues.

Pharmaceutical preparations of this general character have been known and used for some time past in the treatment of various physical defects. For example, they have been injected into, and into the neighborhood of hernia] defects for the purpose of closing the defects and strengthening contiguous structures by producing or stimulating proliferation of connective and/or fibrous tissue. Such injections set up a mild tissue irritation in the margins of the ring or canal through which the hernia protrudes and thus cause these tissues to throw out young fibrous tissue cells orfibro blasts which mature into tough adult fibrous tissue and ultimately close or obliterate the ring orcanal, thereby prohibiting the protrusion of the hernia. These medicinal agents are also commonly used for the obliteration of varicose veins by injecting them into the lumen of the veins and thereby producing an inflammatory reaction resulting in occlusion of the vessel lumen. for the obliteration of hemorrhoids and of naevi by sclerosis of the vascular structures thereof, and for the shrinkage or obliteration of cavities such as hydrocele sacs, bursae, and various types of cysts, as well as soft tissue sinuses.

Among the different agents which have been used for these purposes are phenol, alcohol, zinc sulphate, glucose,. strong sodium chloride solution, tannic acid and extracts containing tannins, urea, quinine, irritating resins and extracts containing them, and irritating mineral acids. Probably the most innocuous agents have been the salts or soaps of the fatty acids of various well known oils, particularly cod liver oil and castor oil. However, all of the substances heretofore studied possess the common serious disadvantage that the reparativeor proliferative process brought about by their injection is secondary to an exudative reaction which is sometimes accompanied by necrosis and even abscess formation. These agents first exert upon the tissue injected a severe irritating action which causes the tissue to throw out a serous exudate or an accumulation of serum containing a large number of polymorphonuclear cells, and repair comes only as a secondary reaction to the initial tissue destruction. Another disadvantageoi the preparations previously known resides in the fact that these agents are in general harmful if introduced into the blood stream, a result which is not unlikely to occur accidentally during their use. For example, it is known that certain of these agents, particularly the soaps made from castor oil and cod liver oil, are hemolytic in character and that their introduction into the circulation is therefore undesirable. It is also known that the acids of castor oil are pharmacologically active and thattheir effects may be deleterious should they find their way into the general circulation. Still another disadvantage of the hernial solutions previously used is that serious complications may'reault from their injection into the peritoneal cavity orinto the hernial sac.

It is therefore one of the objects or the present invention to provide a method capable of producing a pharmaceutical preparation particularly adapted for use in the injection treatment oi structural abnormalities of the human body which will be both highly effective in its intended action and also free of the disadvantages of the various agents hitherto known and used for similar purposes.

Another object is to provide an efiective method for making a pharmaceutical product of novel composition which maybe safely injected into the human body without danger of harmful reaction and which will serve in a remarkably efiective manner as a means of stimulating, the repair of body abnormalities of the types previously mentioned.

A further object is to provide a novel method for preparing a medicinal agent i of new and, unusual character which is especially well adapted for use in the injection treatment of hernia.

Still another object is to provide .a method whereby a new product of the character described may be easily and economically prepared from readily obtainable materials.

These and other objects will appear more fully upon a consideration of the detailed description of the preferred embodiment of the invention which follows.

It has been discovered that a pharmaceutical product of the character sought, possessing unusually desirable features and free from the various disadvantages of the preparations previously known and used for similar purposes, can be produced in a novel and practical manner from the oil of various seeds of the Plantago family, es-

. pecially the blond psyllium seeds known as Plantago ovate or Plantago ispaghula. By setting free the fatty acids of this oil, purifying them, and then causing them to combine with an inorganic or organic basic ingredient to form salts or soaps of the acid and the basic ingredient, a product is obtained which, as has been thoroughly demonstrated by clinical tests, is particularly well adapted for the repair of those abnormalities of the human body which are treated by injecting into the body medicinal agents in the nature of irritants which serve as proliferative stimulants for connective and fibrous tissue, or as obliterative and sclerosing agents for vascular tissue. Although the exact chemical composition of this new product cannot be stated with certainty, it has been determined that its effectiveness as a pharmaceutical agent for the injection treatment of these various physical conditions is due to the presence therein of the salts or soaps of the fatty acids of the oil derived froin psyllium seeds.

In preparing this product, the oil is preferably obtained from the'psyllium seeds by grinding and milling and then extracting the oil with suitable fat solvents in any desired manner. The oil may also be obtained from parts of the milled seeds such as the hulls which are an article of commerce. After clarification the oil is saponified with an alcoholic alkali in the customary manner to produce salts of the fatty acids of the oil. These salts are then acidified, as with hydrochloric acid. Upon acidification the fatty acids are liberated in the form of an oily layer and, being insoluble in water, may be readilycollected and purified by washing with water. The purified fatty acids are next converted to water soluble salts or soaps by combination with an inorganic basic ingredient such as sodium, potassium, or ammonium hydroxides, or with an organic basic ingredient such as triethanolamine or methylamine. The salts may be treated with organic solvents to further remove impurities. The resultant purified salts or soaps are preferably prepared for commercial use in the form of aqueous solutions which may, if desired, also include a small amount of some antiseptic or anaesthetic such as benzyl alcohol. The final solution is usually filtered with animal charcoal before being bottled.

Although it will be recognized by those skilled in the art that the specific steps of the method of the present invention may be varied in certain respects, the following procedure has been found preferable in the practice of the invention. 1200 grams of psyllium seed oil are placed in suspension in 2750 cc. of ethyl alcohol and the mixture is heated in a water bath until the internal temperature is about 50 0. During this operation, it is probable that some of the oil is dissolved. The psyllium seed oil used may be obtained in any suitable manner, as by extraction with fat solvents from milled psyllium seed hulls as previously mentioned. 325 cc. of a cold 50% solution (by weight) of sodium hydroxide are then poured slowly into the heated oil and alcohol while the same is stirred. The resulting mixture is permitted to stand with occasional shaking for approximately fifteen minutes, at the end of which time distilled water is added until the total volume equals 6 liters. The soap solution thus produced is then poured into a solution of 2000 cc. of distilled water and 600 cc. of concentrated hydrochloric acid, accompanied by vigorous stirring. As a result of the acidification, the fatty acids which are insoluble in water rise to the surface and may be readily siphoned of! from the aqueous layer. The fatty acids are then washed with 5 liters of hot distilled water, separated from the washing water, and filtered to remove impurities. 700 grams of the fatty acids thus obtained and 300 grams of benzyl alcohol are then placed in suspension in 13,000 cc. of distilled water, after which a 10% solution (by weight) of sodium hydroxide is added slowly, accompanied by stirring, until the pH of the resulting solution is 8.3 as determined with phenolphthalein as indicator. The solution thus produced is then diluted with distilled water to a volume of 15,000 cc. and finally filtered with animal charcoal to remove any remaining impurities. This final solution, which may be characterized as an approximately 5% aqueous solution of the sodium salts of the fatty acids of an oil of the type obtained from psyllium seeds, is then bottled in sterile containers or otherwise suitably prepared for marketing.

There is thus provided by the present invention a novel and useful method for the preparation of a pharmaceutical product which is particularly well adapted for the treatment of various abnormalities of the human body. The product of this method is different from and superior to those hitherto known and used for similar purposes in that it can be injected intravenously in massive doses without harm, as contrasted with the dangers attending intravenous injection of caustic or escharotic agents, tannins, resins, or metallic salts such as zinc sulphate. Consequently, accidental escape from the site of injection into the general circulation of the body cannot cause serious injury as often results when these other agents are used. It has also been found that the preparation produced by the method of the present invention is less prone to cause hemolysis than are salts prepared from the acids of other oils such as castor oil or cod liver oil, and hence is less likely to cause harm should some of the injected solution find its way into the blood stream. Another of the more important distinctions between the product of the present process and those of the prior art resides in the fact that injection into the body of a solution containing salts of the fatty acids of psyllium seed oil produces a primary proliferation and rapid maturation of connective tissue, whereas the injection of previously known agents produces first an exudative reaction accompanied by tissue necrosis, the proliferation of tissue coming only as a secondary reaction to the primary destruction caused by the injected agent. Clinical tests of this product on human beings have proven that it is highly effective in its action, that it can be freely used without serious ill effects, and that its use causes little or no pain to the patient. These and other advantages of the product, together with the simplicity, ease and economy of the procedure by which it is made, are indicative of the novelty, usefulness and practical importance of the method herein disclosed.

Although only one specific embodiment of the method of the present invention has been described in detail, it will be understood that the invention is not limited to the precise procedure described, but is capable of variation in a number of respects. For example, although it has been found preferable to utilize as the starting material the oil extracted from blond psyllium seeds, the oils obtained from various other seeds of the Plantago family may also be used. It is also contemplated that an oil possessing the same characteristics as psyllium seed oil may be produced synthetically or artificially and used instead of the natural oil. Furthermore, while in its preferred form the product of the present method comprises an approximately 5% aqueous solution of the sodium salts of the fatty acids of psyllium seed oil containing a small amount of be'nzyl alcohol as an anaesthetic, it will be obvious to those skilled in the art that other salts or soaps of the acids may be used, that the benzyl alcohol may be either omitted or replaced by other anaesthetics or antiseptics, and that the concentration of the solution may be varied as desired within those limits which are satisfactory to the medical profession. Moreover, the specifically disclosed product of the method of the present invention, which is thesubject matter of application, Serial No. 76,702, filed April .27, 1936, is not to be considered as limitative of the scope of the invention represented by the method. Reference is therefore to be had to the appended claims for a definition of the limits of the invention.

What is claimed is:

1. A method of preparing a pharmaceutical product adapted for injection into the human body including the steps of forming an aqueous suspension of the fatty acids of the oil obtained from psyllium seeds, and then converting said acids to water soluble salts by adding to the suspension a soluble basic ingredient.

2. A method of preparing a pharmaceutical product adapted for injection into the human body including the steps of forming an aqueous suspension of the fatty acids of the oil obtainedfrom psyllium seeds, and thenconverting said acids to their sodium salts by adding to the suspension a dilute solution of sodium hydroxide.

3. A method of preparing a pharmaceutical product adapted for injection into the human body including the steps of forming an aqueous suspension of the fatty acids obtained from psyllium seed oil, and then neutralizing said acids by adding to the suspension a solubleorganic or inorganic basic ingredient until the pH of the resulting solution is approximately 8.3.

4. A method of preparing a pharmaceutical product adapted for injection into the human body including the steps of forming a suspension of the fatty acids obtained from psyllium seed oil and benzyl alcohol in water,'and then neutralizing said acids by adding to the suspension sodium hydroxide in such amount as to bring the pH of the resulting solution to approximately 8.3.

5. A'method of preparing a pharmaceutical product adapted for injection into the human body comprising the steps of saponifying the oil obtained from psyllium seeds, liberating the fatty acids of said saponified oil by acidification, and

' then converting said acids'into soluble salts.

6. A method of preparing a pharmaceutical product adapted for injection into the human body comprising the steps of saponifying the oil obtained from psyllium seeds, liberating the fatty acids of said saponified oil by acidification,

, collecting and purifying the fatty acids thus obtained, and then converting said acids into solubie salts.

7. A method of preparing a pharmaceutical product adapted for injection into the human body comprising the steps of saponifying the oil obtained from psyllium seeds, liberating the fatty acids of said saponified oil by acidification, collecting and purifying the fatty acids thus obtained, and then converting said acids into their sodium salts.

8. A method of preparing a pharmaceutical product adapted for injection into the human saponified oil by acidification, forming an aqueous suspension of said fatty acids, and then neutralizing said acids by adding to the suspension sodium hydroxide in such amount as to bring the pH of the resulting solution to approximately 8.3.

10. A method of preparing a pharmaceutical product adapted for injection into the human body comprising the steps of extracting from psyllium seed hulls the oil contained therein, mixing said oil with alcohol and heating said mixture, saponifying said oil by adding to said mixture an alkaline solution, acidifying the resulting soap solution and collecting the fatty acids thus produced, forming an aqueous suspension of said fatty acids, and then converting said acids to soluble salts by adding to the suspension a soluble basic ingredient.

11. A method of preparing a pharmaceutical product adapted for injection into the human body comprising the steps of extracting from psyllium seed hulls the oil contained therein, mixing said oil with ethyl alcohol and heating said mixture, saponifying said oil by adding to said mixture 9. cold alkaline solution, acidifying the resulting soap solution and collecting the fatty acids thu's produced, suspending approximately 'l00 grams of said acids and 300 grams of benzyl alcohol in about 13,000 cc. of distilled water, and then adding to the suspension sodium hydroxide solution until the pH of the resulting solution is approximately 8.3.

12. A method of preparing a pharmaceutical product adapted for injection into the human body comprising the steps of extracting from psyllium seed hulls the oil contained therein, mixing said oil with ethyl alcohol and heating said mixture, saponifying said oil by adding'to said mixture a cold alkaline solution, acidifying the resulting soap solution and collecting the fatty acids thus produced, suspending approximately 700 grams of said acids and 300 grams of benzyl alcohol in about 13,000 cc. of distilled water, adding to the suspension sodium hydroxide solution until the pH of the resulting solution is approximately 8.3, diluting the resulting solution with distilled water to avolume of about 15.000 cc., and removing the undesired impurities therefrom.

PHILIP A. KOBER.