METHOD OF IMPROVING PARENTERALLY ADMINISTERABLE PHYSIOLOGICALLY ACTIVE COMPOSITIONS BY INCORPORATING THEREIN AN EPSILON-AMINOCAPROIC ACID OR TRANEXAMIC ACID

Abstract: The method of improving parenterally administerable physiologically active compositions which comprises, incor­ porating in said compositions a small but effective amount of a compound of the formulae, wherein R is H, lower alkyl or acyl; each R¹ is H or lower alkyl; and n is an integer of from 1 to 6; x is 0 or 1; each Y is the same or different and is H or NH₂; and the non-toxic pharmaceutically acceptable salts thereof. The final com­ positions of this invention are also new products thereof.

Description: r hod of improving parenterally administerable Physiologicalls active compositions by incorporating therein an epsilonaminocaproic acid or tranexamic acid. This invention relates to methods of parenterally administering physiologically active compositions to patients and improved compositions useful for such purposes. More particularly, this invention has as its objective improved and novel methods for parenterally administering liquid, physiologically active compositions to patients and to new compositions useful therefor. It is well recognized that there are numerous instances in which physiologically active compositions are required to be parenterally administered to patients. Phsiologjcally active compositions may have to be parenterally administered to patients for either therapeutic or diagnostic purposes and physiologically active components of the compositions can encompass a broad spectrum of active materials including such well known materials as biological derivatives, for example, sera, vaccines, toxoids and anti-toxins, allergens, and allergenic extracts; or chemically derived substances, for example, antibiotics, steroids, central nervous system agents, and other like pharmacologically active chemical substances. When it is determined by the s];illed worker that the physiolo- gically active material to be' administered is best introduced to the patient being treated by a parenteral route, the physiologic ally active material is first incorporated into a suitable paren terally administerable composition for this purpose. This parenterally administerable composition is usua,lly in a liquid form and is usually comprised of a suitable, paren terally administerable non-toxic vehicle, for example, water or a combination of water and alcohol, into which has been in corporated the required amount of the desired physiologically active material. The resultant liquid parenterally adminis tenable physiologically active composition is then administered to the patient by the parenteral route selected by the skilled 'worker, for example, by intramuscular, subcutaneous, intradermal or intravenous route, employing the usual acceptable means for accomplishing this administration, such as a hypodermic needle and syringe. The methods and means of parenterally administering such parenterally administerable compositions to patients are well known to and understood by the worker skilled in the art. On occasion, as a result of the parenteral administration of these physiologically active compositions, the patient suffers various adverse systemic side effects, for example, swelling and inflammation of the skin and subdermal area surrounding the site of parenteral administration. While these localized systemic adverse reactions are usually not severe or frequent, they do occur with sufficient frequency and intensity in the parenteral administration of certain physiologically active materials1 for example, allergenic extracts, insect or snake venoms, certain insoluble antibiotics, and other like materials, to pose a serious problem to the patient being treaty4. Likewise, the incidence iand severity of these adverse reactions may also increase in response to the character of the parenterally administerable vehicle being employed in the final compositions being admin :,i.stered to the patient, for example, vegetable oil vehicles frequently cause such adverse reactions. To date, though many various attempts have been made to reduce or eliminate the occurrence of these adverse reactions, none has been-completely satisfactory. It has historically been widely recognized that various 1 physiologically active compositions which are designed for parenteral administration to patients are susceptible to rapid deterioration. This is especially true in the case of those physiologically active compositions which are in the form of a liquid parenterally administerable composition. The deterioration of these parenterally administerable physiological compositions results in loss of potency or degradation of the physiologically active components thereof. This storage instability and the resulting degradation of physiologically active components of these compositions is most prevalent in those parenterally administerable compositions which employ an aqueous vehicle. In the past, this serious disadvantage of'the degradation and storage instability of the liquid parenterally administerable physiologically active compositions has been sought to be overcome by various means, none of which have proven to be completely satisfactory. SJeretofore, many attempts have been made to solve this instability problem, most of which involve the incorporation into the parenterally administerable composition of substantial amounts of various agents which were supposed to obviate the problem. Among the various agents which have been employed for this purpose may be included such materials as glycerin; polysorbate 80 (poly6xyethylene (20) sorbitan monooleate); dextrose; human serum albumin; aluminum precipitation; siliconization of the vials used to store the compositions; buffered saline solutions, for example,'phosphate- or bicarbonate-buffered; and various other materials, for example, polyvinyl pyrrolidone or polyethylene glycol. To date none of the foregoing has DrojdPd the .cstisfaetory result req0Ired. We have no discovered that the disadvantages suffered b the prior art parenterally administerable physiologically actie compositions may be overcome by the practice of the in stant invention. We have foundthat liquid, parenterally I administerable, physiologically active compositions may be vastly, improved by the incorporation therein of a small but effective amount of a compound selected from the group consisting of EMI4.1 wherein R1 is H or lower alkyl; n is an integer from 1 to 6; x is 0 or 1; each Y is H or NH2; and R is H. lower alkyl or acyl, and the non-toxic pharmaceutical accept able salts thereof. ost preferably. e have found that most satisiactory results are obtained when the liquid, parenterally administerabie physiologically active compositions which are the subject of this invention have incorporated therein a small but effective amount of epsilon- aminocaproic acid or tranexamic aicd, althouFII the other compounds, including such amino acids as lysine. also provide acceptable results. The compounds of this invention have been found to provide satisfactory results when incorporated into the subject liquid parenterally administerable, physiologically active compositions in small but effective amounts. We haSe found that the amounts of the compounds which may be employed herein should be suffi cient to proide a final concentration thereof in the liquid, parenterally administerable, physiologically active composition to be administered to the patient, of from about 0,001M to about 0.5 A5. Preferably, in the practice of this invention the I. compounds of Formulae I may be present in the 1final, liquid. parenterally administerable, physiologically active compositions of this invention in a concentration of from about 0.001N1 to about 0.5AM, and most preferably in a concentration of from about O.1M to about 0.25M, although the other concentrations also provide satisfactory results. The parenterally administerable, physiologically active compositions which may be employed in the practice of this invention include those parenterally administerable composition8 which are stored and/or administered to the patient being treated in liquid form, and which are subject to deterioration, degradation or loss of potency and standing. More particularly, the compositions which may be employed in the practice of this invention ate those which are in'liquid form, for example, solutions, suspensions or mixtures, where the liquid vehicle is one which is a pharmaceutically acceptable liquid vehicle I for parenteral administration, for example, water, oil, alcohol or the like, and which contains a physiologically active agent which is to be parenterally administered to the patient being treated. Parenteral administration of the final ; compositions of this invention may be accomplished by the administration thereof by any of the following routes: sub cataneous, intradermal, intramuscular, intravenous or any other parenteral route ususally employed for this purpose by the skilled worker employing whatever means are commonly used for such purposes, for example, hypodermic needle and syringe, and the like. The physiologically active substances which may be employed in the practice of this invention are those substances which are to be parenterally administered to the patient and include sub stances which are parenterally administered for either thera- peutic or diagnostic purposes. The physiologically active sub stances which may be employed include those biologically active materials which may be of chemical or biological origin and in dude such substances as antibiotics, hormones, steroids, aller genic substances, allergen extracts, sera, toxins, anti-toxins, vaccines, and other like substances. Preferably, in the practice of the instant invention it is desired to employ these physiologically active substances which are derived from bio logical sources for example, antibiotics, allergenic materials and extracts, biological extracts, for example, vaccines, sera, and anti-toxins, for it has been determined that such biologically originated materials are most susceptible to storage instability and degradation. The amounts of the physiologically active substances which may be employed in the practice of this invention are those which are normally administered to the patients for the condition being treated or the purpose required, and.will depend on the factors usually determined by the skilled worker to control the amounts of the substance being employed. The final compositions of this invention may be prepared in any manner considered suitable by the skilled worker practicing the invention. The individual components of the final compositions of this invention may be admixed to form the desired compositions, or in some instances where the physiologically active substance is in a dry state, for example, as a result of lyophilization, the said physiologically active substance may first be reconstituted by the addition of the desired liquid vehicle, for example, water, and the required amounts of the compounds of Formulae(I) then incorporated, for example, by admixing, to yield the final stable final compositions of this invention. The thus storageably stable final compositions mag then b held for future use. The term 11alkyl'1 as employed herein shall mean and include those alkyl moieties generally considered lower alkyl groups which contain six or less carbon atoms. The acyl moieties which may be employed in the practice of the instant invention include those acyl groups derived from hydrocarbon carboxylic acids of twelve carbon atoms or less, such as, alkanoic acids, cycloalkanoic acids, monocyclic aryl carboxylic acids and the like. The invention may be further illustrated by the following examples: Example 1 Grass pollen extract ( Lolium perenne) (commerically available from HAL Allergenen Laboratorium B.V., Haarlem, Holland) was admixed with 10 ml. of pyrogen-free, distilled water. To the resultant solution was added with mixing, epsilon-aminocaproic acid until the resultant concentration thereof in the final solution was O.1M. The resultant final composition was then divided into individual parenterally administerable doses of 0.05 ml. each. Example 2 The procedure of Example 1 was followed except that an equivalent amount of house dust mite extract (commercially available from HAL Allergenen Laboratorium B.V.) was substituted for the grass pollen extract, yielding equivalent results. Example 3 The procedure of Example 1 may be followed except that an equivalent amount of tranexamit acid or lysine, respectiely, may be substituted for epsilon-aminocaproic acid, with like results. Example 4 The procedure of Example 1 may be followed except that equivalent amounts of antibiotics, for example, penicillin G, cephalosporin, tetracycline or oxytetracycline; vaccines, for example, pertussis, typhoid, anti-rabies, or ye) low fever accine; anti-toxin, for example, tetanus anti-toxin, mn) tl substituted for the grass pollen extract, with similar results. Example 5 In vivo tests were performed employing the parentera) compositions of this invention. Grass pollen allergen extract and house dust mite.allergen extracts were prepared in accord ance with the procedures set -forth in Example 1. In addition. as controls, compositions were prepared in accordance with the procedures of Example 1 and 2, except that sodium phosphate was- substituted for epsilon-aminocaproic acid-to a concentration of 0.15x.1; The final parenterally administerable extracts had the following compositions: A. Grass pollen allergen in pyrogen-free distilled water containing 0.1M epsilon-aminocaproic acid. B. Grass pollen allergens in pyrogen-free distilled water containing 0.15'.! sodium phosphate. C. House dust mite allergens in pyrogen-free distilled water containing O.lM epsilon-aminocaproic acid. D. House dust mite allergens in pyrogen-free distilled water containing 0.15M sodium phosphate. The respective final extracts (O.Q5ml) were intradermallN injected into the test subjects forearms at various sites at premea,sured distances from each other. These skin tests were read fifteen minutes after administration. The xbeal and flare reactions were delineated on a transparent sheet and the mean square wheal diameters (d2 > h) were calculated. The results are set forth in Table 1 and show that there is a significant decrease in the local adverse reactions involved in the administration of the compositions of this invention. TABLE 1 EMI9.1 In addition, the final extracts were also intradermally injected into subjects' forearms at arious sites at premeasured distances from each other over an extended period of time after preparation. In the case of Compositions A and B, these tests were made over a period o 211 days after preparation of the compositions; and in the case of Compositions C and D, over 210 days after preparation. Each skin test uas read fifteen minutes after the administration thereof. The wheal and flare reactions which is a measure of the potency of the extract composition's allergenicity, uere delineated on a transparent sheet and the mean square wheal diameters (d2wh) were calculated. The results set forth on Tables 2 and3 3 below demonstrate that while there is a consistent and persistant degradation in the potency of prior art compositions, the compositions of this invention have little or no potency loss over an extended period of time. TABLE 2 EMI10.1 Patients TABLE 3 EMI10.2 Example 6 In vitro experiments were performed to demonstrate the improved storage stability of the compositions of the instant Invention. A grass pollen extract ( Jolium perenne) containing 50.000 NU in 502 glycerol was held at -700C until diluted from 2000 NU in a series of dilutions don to 31 NU, in the following: compositions: P. Grass pollen with O.154M phenolated phosphate, pH=7. B. rasps pollen with phenolated phosphate containing 0.l?I epsilon-aminocaproic acid. Allergen coupled cellulose discs were made in accordance with the RAST method (A.B. Pharmacia, Sweden) using a bicarbonate buffered Lolium perenne extract. A RAST positive sera was used in RAST inhibition tests which were performed on the subject cdirpositions to determine their activity. The results which demonstrate the reduction in the degradation by freezing and thawing of the instant compositions are set forth in Table 4. TABLE4 elative Activity Extract A 1.0 1.0 1.0 Extract B 1.6 1.5 1.7 The above results demonstrate the relative activity of Extract 'B compared to Extract A and show that the activity of Extract B is substantially greater than that of Extract A. Example 7 The extract compositions prepared in Example 6 and con taining 2000 NU of grass pollen allergens were then divided into 5 equal portions. One portion was employed as a control and the other four portions were incubated for 6, 24, 48 hour.; and 7 days respectively, at 370C. At the end of each time period the test composition was tested in accordance with the RAST inhibition method to determine the relative potencies thereof. The results, which show that the compositions of this invention are more potent than those of the prior'art,-are set forth in Table 5 below. TABLE 5 RAST Potencies After: O Hrs. 6 Hrs. I Day 2 Days 7 ilayc; Extract A 1.0 0.70 0.42 0.41 0.l' Extract B 1.0 0.94 '0.65 0.52 0.22 These results demonstrate that the shelf life of Extract B is approximately twice that of Extract A. Example 8 The procedure of Example 7 was repeated except that the extracts ere stored at a temperature of 40C. for 1, 3 and 6 months. The-results obtained are set forth in Table 6. TABLE 6 RAST Potencies After: O Month 1 month 2 Months 3 Months Extract A 1.0 0.77 0.55 0.36 Extract B 1.0 0.57 p.32 0.26 The foregoing results demonstrate that the shelf life of Extract B is approximately three times that of Extract A. Example 9 To several patients, two different dosages of Extracts C and D of Example 5 were administered. The initial dosage had a potency of 5 Noon Units (NU) while the second was increased tenfold to 50.NU. The difference in the skin reactivity as a result of the two administrations was, measured in accordance with the method set..forth in Example 5. The results set forth in Table 7 clearly show that the use of the compositions of the instant invention maintain a dose dependent reaction in a group of patients. TAtfl EMI13.1 In addition to the foregoing, it must be noted that the etiology and root causes of the multitude of individual diseases or conditions included within the generic definition of allergy are not completely known at this time. The generic condition known in medicine as "allergy" connotes an altered reaction of tissues or other systemic parameters in certain persons on exposure to certain agents which, in similar amounts are innocuous to other persons. These altered reactions of the allergic person may be of various types, ranging from a more or less intense skin sensitivity to a sere and ; sometimes fatal systemic shock reaction. At the present time it is the consensus of the medical world that the allergic reactions suffered by all susceptible persons are mediated, if not basically caused by various exciting agents, commonly referred to as "allergens" or "antigens". The presence of these allergens cause, in those individuals who are sensitive to the specific allergens involved, the production of specific antibodies or sensitized cellos. The interaction of antibodies with allergens by some mechanism not fully appreciated, cause allergic symptoms. Common manifestations of the type of allergic symptoms usually seen in persons suffering a so-called immediate-type "allergic attack" are such conditions as "hat fer" i.e., runny nose and watery eyes, asthmatic re actions, gastrointestinal disturbances, urticaria edema and shock. A person who is allergic may be sensitive to only one allergen, but multiple sensitivities are the rule. .The various types of allergens to which a patient may be susceptible are found in such allergic materials as in halants, for example, pollens, fungi, vegetable or animal epithela, cosmetics, and house dust components; foods, for example, eggs, shellfish, and strawberries; infectious agents2 for example, bacteria, fungi, molds, parasites, such as, mites, ticks or fleas; and contactants, for example, plants, flowers, chemicals, furs, and cosmetics. These allergic materials may contain one or more allergens to which the patient 'is sensitive and exposure to these allergic materials will, in 1 the susceptible individual, cause an allergic attack, manifested one b one or more allergic symptoms, the severity of which depends I: upon the degree of exposure as well as the nature of the allergic material to which tbe patient is exposed. It is important to determine the types of allergic materials and/or allergens to which the allergic person is susceptible. This determination is required in order to know which allergic materials the patient is to be isolated from as well as to ascertain the type of treatment which wil be required to prevent, ameliorate or therapeutically teat the patient. The diagnostic procedures that hae been developed to date include one that is most commonly employed to determine the identity of the aller- gens to which the patient is sensitive, the skin test. In the skin test, diagnostic procedure a small amount of an extract of the allergen is administered cutaneously to the patient and the local allergic reaction, i.e., wheal and flare, observed to determine the patients sensitivity to the test allergen. Once the identity of the allergens to which the patient is sensitive has been determined, the type of therapeutic treatment required to prevent future allergic attacks can be decided upon. Where the total elimination of the allergen from the presence of the patient is not feasible, for example, where the allergen is a pollen or house dust component, one of the prime methods of treatment is that of desensitiation or hiposensitization. This method of treatment involves the successive injecting of an extract of the'causitive allergen in a series of gradually,in creasing doses until the patient slowly builds up an immunity threshold which will permit exposure to a normal concentration of the allergen without the initiation of an allergic attack. As noted above, the allergen extracts presently employed have the ability to degrade and lose substantial potency within a short time after their production or reconstitution, if they are stored in the dried state for later use. In addition, desensitization procedures must be carried out with great caution, especially in those cases where the allergen is highly potent or the patient is extremely sensitive, as severe reactions may result. The reactions involved may range from severe local reaction and swelling at the site of injection to severe systemic reaction, including anaphylactic shock and death. We have now discovered a process of producing the allergen containing extracts adapted for systemic administration to patients and which are suitable for use in the diagnosis and which are suitable for use in the diagnosis and therapeutic treatment of allergic conditions while avoiding the above noted disadvantages. We have found that an allergen containing extract composition may be produced by extracting an allergic material with a suitable solvent which has incorporated therein a small but effective amount of the compounds of this invention. The allergic material which may be employed in the practice of this invention may be those materials which contain allergens to which patients are sensitive and which are noted above. The suitable retraction solvent which may be employed in the practice bf the instant invention may be any solvent which sill satisfactorily extract the allergens from the allergic material, and/or which will be suitable for systemic administration to the patient being treated, or alternatively is capable of being completely removed from the extracted allergen-containing composition prior to its administration to the patient. !lost preferably, it has been found that-an aqueous solvent provides the most satisfactory result in the practice of this invention. However, the instant invention may be practiced by employment of any suitable solvent which can be used for the purposes required, including alcohols, such as ethanol; pyridine/aqueous alkaline extraction solutions; tnd other like solvents which are known to the skilled worker to be useful for such purposes. The satisfactory practice of the instant invention requires that a small but effective amount of the-compounds of this invention be incorporated in the solvent of extraction. By a small but effective amount it is hereby meant that the final concentration of the compound in the extraction composition should be between about 0.001)1 and 0.5M, and preferably between 0.025M and 0.4, and most preferably between 0.05 and 0.2M, although the other concentrations may ,also provide satisfactory results. The compounds which are most preferably incorporated in the extraction solvent of the instant invention are those of the formula, EMI17.1 wherein each Y may be H or lower alkyl; 7. is'CH2; n is O or 1; -m is O or 1; -w is CH2 or CENH2; R is an,alkyle,ne group of the formula CrH2rt wherein r is an integer of from 4 to 8; X is H, acyl or lower alkyl; and the non-toxic pharmaceutically acceptable salts thereof. It has been found the optimum results are obtained when the compound employed is either 6-aminohexanoic acid, or trans-4(aminomethyl) cyclohexanecarboxylic acid, commonly known as epsilon-aminocaproic acid or tranexamic acid, respectively. The conditions under which the extraction of the allergic materials may be conducted are those under which such extraction procedures are usually performed, as is well known to the skilled worker. Thus, the extraction Procedures may be performed at any temperature or under such atmospheric conditions as may provide the most optimum results as is appreciated by the skilled worker. The allergen containing extract composition obtained by the extraction of the allergic material with the solvent composition of this invention may then be treated in the same manner as any allergen containing extract. Thus, the allergen containing extract mag be employed directly for diagnosis of therapeutic treatment of patients having an allergic condition, particularly in the case of diagnostic purposes any local reaction which is not of diagnostic importance will be inhibited; or alternatively, the said allergen containing extract may be further treated to obtain a composition having a higher, although innocuous, co of allergens; or as a further alternate the allergen containing extract may be taken don to dryness by any suitable procedure known to the skilled worker to accomplish this result without injury to the allergens, for example, lyophilization, for storage and reconstitution at a later date just prior to administration to the patient. The instant invention may be further illustrated by the following exampl.es: Example 10 An extraction solution comprised of pyrogen-free distilled water containing 0.1M of epsilon-amino caproic acid, and having a pH of 7.0 was prepared. The resultant extraction solution was then employed to extract the allergens of Lolium perenne pollen, which was carried out under normal laboratory ,conditions of temperature and pressure to yield an allergen-containing extract solution having incorporated therein approximately 0.1M of epsilon amino caproic acid. To this final allergen containing solution was added a small amount of phenol as a preservative. The foregoing procedure may be followed except that 0.001M and 0.5M of epsilon-amino caproic acid is substituted for the 0.lM employed, with like results being obtained. The foregoing procedure may be followed except that equivalent amounts of house dust components, mites, molds, ragweed pollen and animal danders may be employed in place of the Lolium perenne pollen to obtain like results Example 11 In vitro tests to determine the specificity and potency of the allergen-containing extracts of the instant invention were conducted as follows: An amount of grass pollen (Lolium perenne) was extracted with extraction solutions of the following compositions: 1. Pyrogen-free distilled water containing 0.lM sodium bicarbonates pH = 7.0 2. Pyrogen-free distilled water containing 0.154M sodium phosphate, pH 5 7,0 3. Pyrogen-free distilled ;water containing 0.1M epislon aminocaproic acid (EACA), pH = 7.0. The resultant extracts were then tested on cellulose discs prepared and assayed according to the RAST method (RAST assay method commercially available from AB Pharmacia, Sweden) according to the following general procedure: .Fifty micro-liters of inhibiting extract was incubated with 50 microliter ofa highly positive grass pollen serum pool. After 3 hours of incubation, Lolium perenne allergen coupled discs were added to the tubes. After 6 hours of incubation, discs were washed 3 times and incubated with 50 microliter of radiolabelled anti IgE for at least 6 hours. After washing, radioactivity was measured in a gammacounter and the % of inhibition was calculated. RAST values for 6 individual sera were determined with discs coupled to Lolium perenne extract produced with Extraction solutions 1, 2 and 3, with discs obtained from AB Pharmacia serving as a control. Results are shown in Table 1. RAST values were determined for various dilutions of a positive serum pool with discs coupled to Lolium perenne extract produced with Extraction solution 1 and 3. Results are shown in Table 2. Extracts made with Extraction solutions 1, 2 and 3 were assayed by the RAST inhibition method. Results are shown in Table 3. The results of these tests demonstrate that the compositions of the instant invention have the same potency as the prior art compositions. TABLE 1 EMI21.1 EMI21.2 TABLE 3 EMI21.3 Example 12 The procedures of Example 1 may be followed except that an equivalent amount of tranexamic acid is substituted for the epsilon-amino caproic acid with like results being obtained. The invention may be variously otherwise embodied within the scope of the appended Claims.

Claims: CLAIMS 1. A composition suitable for parenteral administration, which comprises a physiologically active composition in paren terally administerable form having incorporated therein a small but effective amount of a compound selected from the group consisting of compounds of the formulae: EMI23.1 wherein R. is H, lower alkyl or acryl; x is 0 or 1; each Y is H or NH2; R1 is H or lower alkyl; and n is an integer of from 1 to 6; and the non-toxic pharm3ceuticall- acceptable salts thereof. 2. The method of improving the storage stability of paren terally administerable physiologically active compositions which comprises incorporating in said compositions a small but effective amount of a compound selected from the croup consisting of compounds of the formulae: EMI23.2 wherein R. P1 and n are as defined in Claim 1. 3. The composition of Claim 1 wherein the compound is epsilon- aminocaproic acid. 4. The composition of Claim 1 wherein the physiologically active composition is an allergenic extract. 5. The composition of Claim 1 wherein the physiologically active composition is an allergenic extract, an antibiotic, a steroid or a vaccine. 6. The method of claim 2 wherein the compound is epsilon aminocaproic acid or tranexamic acid. 7. The method of Claim 2 wherein the physiologicall,y active composition is an allergenic extract. 8. The method of Claim 2 wherein the phNsio1Ogicallt active composition is an allergic extract, a steroid, an anti biotic or a vaccine. 9. A method of producing allergen containing extracts adapted for systemic administration to patients and which are suitable for use in the diagnosis or ther apeutic treatment of allergic conditions, which com prises first extracting allergic materials with a suitable solvent having incorporated therein a small but effective amount of a compound of the formula, EMI24.1 wherein Y is H or lower alkyl; Z is CH2; n is O or 1; R is alkylene or cycloalkylene; X is H, acyl or lower alkyl; m is O or 1; W is CH2 or CHNlI2; and the non toxic, pharmaceutically acceptable salts thereof; and F obtaining the allergic containing extract thus produced. 10. The method of Claim g wherein the compound is 6-amino hexanoic acid or trans-4 (aminomethyl) cyclohexane - carboxylic acid. ii The method of Claim 9 wherein the compound is present in a concentration of from 0.001 to 0.5 M.

Inventors: STEVENS, ERIC, VAN HOEYVELD, ERNESTINA MARIA
Applicants: TETRA CONSULTANTS INC.
Application year: 1983
Main classification: A61K47
IPC codes: A61K47