GB1580444A - Pharmaceutical compositions - Google Patents

Pharmaceutical compositions Download PDF

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Publication number
GB1580444A
GB1580444A GB214577A GB214577A GB1580444A GB 1580444 A GB1580444 A GB 1580444A GB 214577 A GB214577 A GB 214577A GB 214577 A GB214577 A GB 214577A GB 1580444 A GB1580444 A GB 1580444A
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linolenic acid
dihomo
composition
functional derivative
physiologically functional
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BIO OIL RES
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BIO OIL RES
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/21Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic, hydroximic acids
    • A61K31/19Carboxylic acids, e.g. valproic acid
    • A61K31/20Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids

Description

(54) PHARMACEUTICAL COMPOSITIONS (71) We, BIO-OIL RESEARCH LIMITED, a British Company of 30 Hornby Drive, Nantwich, Cheshire CW5 6JP, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to pharmaceutical compositions which are potentially useful as anti-thrombotic agents.

Thrombosis may occur in the venous or arterial vessels. In the former, coagulation and fibrin deposition are probably the most important features and treatment is usually aimed at lysis of the deposit or its removal by surgery followed by the prophylactic use of anticoagulant drugs. In the arterial vessels, fibrin probably plays a secondary role, the initiating factor being the adhesion of platelets to the vessel wall either to the exposed sub-endothelial collagen or some preexisting vascular deposition or lesion. This adhesive stage is followed by the local release of intracellular platelet factors which induce further adhesion and aggregation of platelets.

Fibrin and probably lipids are thereafter deposited with a progressive build-up of a mural thrombus which may embolise or finally occlude the circulation in the parent or other artery most frequently in the coronary or cerebral circulation.

Blood lipids are known to be involved in both venus and arterial thrombosis not only for their role as an integral part of the occluding thrombus but also as inhibitors of the fibrinolytic enzyme system, as a major source of abnormal platelet function and possibly the mediators of the arterial damage which first initiates platelet deposition on the intima.

The compound dihomo-y-linolenic acid has been observed to possess platelet aggregation inhibiting activity in tests carried out in vivo on rats, rabbits and dogs (see for example (1) Willis A. J., Comai K., Kuhn D. C. and Paulsrud J., 1974, Prostaglandins, Vol. 8, pages 509-519 and (2) Rose J. C. Johnson M., Ramwell P.

W. and Knott, P. A., Proc. Soc. Experimental Biol. Med., 1975, Vol. 148, pages 1252-1256).

The effective dosages administered per gram body weight of the test animals would however represent a very high equivalent dosage for human use, and even if such a high dosage were acceptable the cost would in practice be prohibitive having regard to the fact that dihomo-y-linolenic acid is an expensive substance at the present time.

It has now been discovered that y-linolenic acid also possesses platelet aggregation inhibiting activity and that the platelet aggregation activity of dihomoy-linolenic acid is exhibited at lower dosages than was hitherto thought to be the case. Thus pharmaceutical compositions containing both y-linolenic acid (which is a less expensive substance than dihomo-y-linolenic acid) and dihomo-y-linolenic acid as active ingredients are potentially useful as anti-thrombotic agents.

According to one feature of the present invention, there is thus provided a pharmaceutical composition for use as an antithrombotic agent which comprises effective amount of both a) y-linolenic acid or a physiologically functional derivative thereof, and b) dihomo-y-linolenic acid or a physiologically functional derivative thereof.

Convenient physiologically functional derivatives of y-linolenic acid and dihomo-y-linolenic acid for incorporation in compositions according to the invention include the C1-C4 alkyl (e.g. methyl and ethyl) esters and the glycerides of the acids.

If desired, the pharmaceutical compositions according to the invention may be produced by associating pure y-linolenic acid (or a functional derivative thereof) and pure dihomo-y-linolenic acid (or a functional derivative thereof) with an acceptable pharmaceutical vehicle. It will however generally be convenient to incorporate the y-linolenic acid into the pharmaceutical compositions in the form of an oil having a high y-linolenic acid content.

At the present time known sources of oils having a high y-linolenic acid content are few. One source currently available is the seed of the Evening Primrose or Oenothera biennis L. the oil extract therefrom containing y-linolenic acid and linoleic acid in the form of their triglycerides. Another source of y-linolenic acid is the seed of Borage Officinalis which provides a richer source of y-linolenic acid with smaller amounts of linoleic acid. Recent studies on fungi which can be cultivated by fermentation promise a fungal oil source.

The seed oil extracts referred to above can be used as such or can if desired be fractionated to yield an oily composition containing the triglycerides of y-linolenic acid and linoleic acid as the only fatty acid components, the y-linolenic acid content being for example as high as GQ /n The presence of the triglyceride of linoleic acid in the pharmaceutical compositions according to the invention produced from the above-mentioned seed oil extracts is acceptable. Moreover it is believed that the use of such seed oil extracts may have a stabilising effect upon the dihomo-y-linolenic acid or physiologically functional derivative thereof incorporated therein.

The dihomo-y-linolenic acid or physiologically functional derivative thereof is conveniently added to the seed oil extract (or other source of y-linolenic acid) in the desired concentration. The on extract containing the dihomo-y-linolenic acid physiologically functional derivative thereof can then be processed by conventional methods into appropriate pharmaceutical compositions by admixture with an acceptable pharmaceutical vehicle therefor. The pharmaceutical composition is preferably processed into dosage unit form, each dosage unit being adapted to provide a fixed dose of active ingredient. The composition is conveniently in a form suitable for oral, rectal, parenteral or topical administration.

The term "pharmaceutical vehicle" is used herein to embrace the wide variety of modes of presentation which may be adopted with the active materials, and is qualified with the term "pharmaceutical" so as to exclude any possibility that the nature of the compositions, considered of course in relation to the route by which they are intended to be administered, could be harmful rather than beneficial.

Without detraction from the generality of the foregoing definition of the term "pharmaceutical vehicle", it can be stated for purposes of guidance that, subject always to the exclusion of ingredients of a toxic or otherwise noxious nature, or which would interfere with the pharmacological actions of the materials, the term may be regarded as having the following particular meanings in relation to the modes of administration identified below.

a) So far as oral administration is concerned, the term means the ingestible coherent solid excipient of a tablet or coated tablet, the ingestible container of a capsule or cachet, the ingestible and usually flavoured pulverulent solid carrier of a powder or granulate, or the again usually flavoured ingestible liquid medium of a syrup or elixir. In general, since the active materials are nurmally liquid, the vehicle will be suitable for the presentation of a liquid and will be a diluting, dispersing, surface active, suspending, binding, lubricating, flavouring, preserving, thickening or emulsifying agent.

b) So far as administration by injection is concerned, the term means a sterile injectable liquid solution or suspension medium, preferably isotonic with the body fluids encountered in the vicinity of the intended site of injection. In general, the vehicle will be an anti-oxidant, buffer, bacteriostat, solute which renders the composition isotonic with said body fluid, suspending agent or thickening agent.

Moreover, an extemporaneous injection solution or suspension may be prepared from sterile powders, granules or tablets.

Whilst the modes of presentation just listed represent those most likely to be employed, they do not necessarily exhaust the possibilities and for example rectal administration and topical application to the skin and nails are also envisaged.

However, the preferred method of administering the active materials is orally, a particularly preferred mode of presentation at present being in the form of capsules.

Conveniently the compositions are prepared by admixture.

Powders for oral administration may be prepared by forming a homogeneous dispersion of the active material in an ingestible pulverulent solid carrier, either by mixing and grinding it with the carrier, or by first pasting the pulverised carrier with the active material itself, or with a solution of the material, and then drying.

Examples of suitable inert materials for inclusion as the carrier are calcium carbonate, calcium silicate, talc, calcium sulphate, kaolin, hard paraffin, beeswax, kieselguhr and magnesium stearate. These can be replaced or supplemented by binders such as sugar, starch, lactose and pectin. Flavour can be imparted to the powder by incorporation of sugar and/or aromatic substances such as soluble cocoa powder. When the pulverulent solid carrier is pasted with a solution of the desired active material, the solvents employed may include water, alcohol, chloroform and sorbitol, as may be appropriate.

Tablets may be prepared by compressing the powders just described into coherent shapes of the appropriate size. To facilitate the manufacturing operation before compression the powders may advantageously be mixed also with binders and/or lubricants, such as starch, pectin, gelatin, gum arabic, methylcellulose, carboxyl-methyl cellulose (preferably in the form of its sodium salt), talc, stearic acid and magnesium stearate, if these are not already present. The coherent tablets thus formed may be coated, for example with sugar to improve their appearance, taste and durability, and may, moreover, be scored to facilitate administration of smaller doses, if desired.

Capsules may be prepared by enclosing the active ingredient, if desired microencapsulated under a nitrogen atmosphere, within a casing or sheath formed of gelatin, glycogelatin or other suitable material. The nature of this material is chosen in relation to the point in the digestive system at which it is desired to release the active material. It is conveniently either of melting point less than body temperature, or soluble in gastric juices, thus, for example, at pH's of 2 or less, or 9 or more.

Syrups and elixirs may be prepared by dissolving or suspending the active material in aqueous liquid media, which may contain a sweetening agent such as a sugar, saccharin or a polyhydric alcohol like glycerol or sorbitol, or another flavouring agent, such as alcohol, chloroform, citrates, or of course both. In the case of suspensions, surface-active agents such as glyceryl monostearate, aluminium monostearate and/or ethyl oleate may be incorporated to maintain the suspension, and solubilizing agents may be employed in solutions, together with suitable co-solvents such as alcohols, chloroform and trichloroethylene, if these are not already present. The thixotropy and viscosity of the liquid medium may be adjusted by the inclusion of appropriate amounts of pectin, gelatin, gum tragacanth, carboxy-methyl-cellulose, or agar-agar. Colourants may also be incorporated.

Injectable preparations may be prepared by forming solutions and/or suspensions in any of the usual sterile media, which may be oily or aqueous.

Injectable solutions of hydrolysed oil may be prepared using albumin to solubilise the free acid. Preferably the preparations are rendered isotonic with the body fluids, and adjusted to the desired viscosity.

Advantageously a preservative such as a-tocopherol is incorporated into the preparation. a-Tocopherol in a concentration of about 0.1 /" by weight has been found suitable for the purpose.

The pharmaceutical compositions according to the invention for rectal administration can be in the form of suppositories which conveniently contain conventional carriers used for this purpose such as for example neutral fats or polyethylene glycol or derivatives thereof.

The pharmaceutical compositions according to the invention for topical application to the skin and nails can for example be in the form of a cream or lotion, again containing conventional carriers as desired.

It will be understood that the absolute quantity of active ingredients presents in any dosage unit should not exceed that appropriate to the rate and manner of administration to be employed but on the other hand should also desirably be adequate to allow the desired rate of administration to be achieved by a small number of doses. The rate of administration will moreover depend on the precise pharmacological action desired.

The compositions according to the present invention for oral administration are conveniently in the form of capsules containing the oil extract as such or in micro-encapsulated form.

The platelet aggregation inhibiting activity of the methyl ester of y-linolenic acid, the methyl ester of dihomo-y-linolenic acid and compositions containing esters of both y-linolenic acid and dihomo-y-linolenic acid has been demonstrated in the following in vitro and in vivo pharmacological studies.

Materials and Methods The following test materials were used: 1. In vitro studies: y-linolenate methyl ester (98% pure) and dihomo-ylinolenate methyl ester ( > 99 /" pure).

2. In vivo studies in the baboon: capsules each containing 0.35 g of an oil ("oil of Evening Primrose") extracted from the seeds of Evening Primrose (Oenethera biennis/Lamarkiana) as hereinafter described in the Examples, the oil extract containing 70% linoleic acid and 7% y-linolenic acid, predominantly in the form of their triglyceride esters, with dihomo-y-linolenate methyl ester added to the oil extract in the quantities hereinafter indicated.

Collection of blood For platelet aggregation studies blood was withdrawn from the femoral vein (baboon, Papio cynocephalus) and from the antecubital vein (human) into a plastic syringe containing trisodium citrate solution (final concentration 0.38%, 0.19% for human plasma). Platelet-rich plasma (PRP) was prepared by centrifugation of the whole blood at 120 g and removal of the supernatant via a siliconed pipette into a plastic container.

Platelet Aggregation Studies A modification of the Born turbidimetric technique (Born, G.V.R., Aggregation of blood platelets by adenosine diphosphate and its reversal, Nature (Lond), 194, 927, 1962) was used. 0.2 ml of PRP was stirred at 370C in a microaggregometer (A.D.G. Instruments Ltd., Codicote, Herts) and titrated with standard solutions of adenosine diphosphate (ADP) as described previously (Sim, A. K. McCraw, A. P. and Sim, M. F., An evaluation of the effect of flurbiprofen [2 (2 - fluoro - 4 - biphenylyl)propionic acid] on platelet behaviour, Thrombos. Res., 7, 655, 1975). That concentration of ADP which was just sufficient to induce a biphasic aggregation response was used as control for each PRP sample.

In vitro the methyl esters were added in decreasing concentrations to PRP until no inhibitory effect on aggregation could be observed.

In vivo the ADP concentration was increased from that used as control until a similar, irreversible aggregation of platelets could be achieved. The difference in concentration of ADP between the control (before dosing) and that which was required to induce irreversible aggregation after dosing gave an indication of the inhibitory effect of the test substance at the time of blood withdrawal.

In Vivo Studies in the Baboon Baboons (Papio cynocephalus) were selected from a small colony of animals whose platelets were known to be relatively sensitive to ADP and other aggregating agents. This and other possible "thrombotic" phenomena have been observed to occur spontaneously in approximately 6% of 500 animals examined in this laboratory.

Three such baboons were dosed orally with capsules containing Oil of Evening Primrose plus dihomo-v-linolenate methyl ester according to the following regime.

Day i: Capsules plus 100 mg dihomo-y-linolenate methyl ester, (15.4 mg/kg).

Day 8: 2 Capsules plus 25 mg dihomo-y-linolenate methyl ester, (3.9 mg/kg).

Day 15: 2 Capsules plus 12.5 mg dihomo-y-linolenate methyl ester, (1.9 mg/kg).

All three animals weighed approximately 6.5 kg and two were male and one was female. Blood samples were withdrawn before dosing (days I, 8 and 15) and at 3 hours after each dosing. The effect of ADP-induced platelet aggregation was evaluated in all samples.

Results Platelet Aggregation In Vitro The inhibitory effect or y-linolenate and dihomo-y-linolenate methyl esters on ADP-induced aggregation of human platelets in vitro is shown in Figs. I (a) and (b) of the accompanying drawings. Dihomo-y-linolenate appeared to be the more potent ester-by an estimated ratio of approximately 2:1.

Platelet Aggregation Studies in the Baboon The effect of 3 different oral dose levels of dihomo-y-linolenate methyl ester (100 mg, 25 mg and 12.5 mg) combined with 0.7 g Oil of Evening Primrose (i.e. two capsules) on ADP-induced platelet aggregation is shown in the following Table.

TABLE Effects of dihomo-y-linolenate methyl ester combined with Oil of Evening Primrose (p.o.) on ADP-induced platelet aggregation in the baboon.

Minimum ADP concentration for secondary aggregation Baboon (uM final conc) blood 3 hours Dose sample Pre-dose after dosing 0.7g Oil of Evening Primrose A (male) 2.5 12.5 + B (female) 0.4 2.0 100 mg dihomo-y- C (male) 7.0 35.0 linolenate (Day I ) 0.7g Oil of Evening Primrose D (male) 1.0 5.0 + E (female) 0.3 0.6 25 mg dihomp-y- F (male) 5.0 25.0 linolenate (Day 8) 0.7g Oil of Evening Primrose G (male) 1.5 7.5 + H (female) 0.35 0.35 12.5 mg dihomo-y- K (male) 7.0 35.0 linolenate (Day 15) There appeared to be a similar potent inhibition of ADP-induced platelet aggregation at all levels of dihomo-y-linolenate. The effect was apparently more marked and regular in the male animals, suggesting a possible sex difference in response to the test material.

It has thus been demonstrated that both y-linolenate and dihomo-y-linolenate compounds are potent inhibitors of ADP-induced platelet aggregation in vitro and moreover that compositions containing both y-linolenate and dihomo-y-linolenate compounds are potent such inhibitors in vivo. On theoretical grounds, it is to be expected that y-linolenate compounds will be slower acting than dihomo-ylinolenate compounds, y-linolenic acid being a precursor of dihomo-y-linolenic acid in the metabolic chain and dihomo-y-linolenic acid itself being regarded as a probable precursor of the compound(s) responsible for the platelet inhibitory activity observed in vivo. Although there is no wish to be limited by any theoretical considerations, it is thus anticipated that adminstration of the compositions according to the invention will be useful both for acute treatment (dihomo-ylinolenate compounds) having a potent inhibitory effect, of rapid onset, upon administration of relatively small doses) and for prophylactic treatment (ylinolenate compounds also having a potent inhibitory effect believed however to be of somewhat slower onset).

It has furthermore been demonstrated that the compositions according to the invention have useful lipid and cholesterol regulating activity.

The compositions of the present invention for oral administration preferably contain as a minimum single dosage of dihomo-y-linolenic acid or physiologically functional derivative thereof at least 40 mg with a particular preference for dosages of at least 60 mg or, for females in view of an observed sex difference, at least 80 mg. y-Linolenic acid and its physiologically functional derivatives are thought to be somewhat less active, and thus the minimum single dosage of y-linolenic acid or physiologically functional derivative thereof will advantageously be at least 60 mg with a particular preference for dosages of at least 80 mg or, for females, at least 100 mg. It is convenient to formulate one type of capsule alone in order to provide a desired single dosage for oral administration, and such a composition will desirably have the following active ingredient contents: Particularly Preferred Advantageous advantageous active active active ingredient ingredient ingredient content content content Dihomo-y-linolenic acid (or physiologically functional derivative 40--250 mg 6150 mg 80150mg y-Linolenic acid (or physiologically functional derivative) 60-500 mg 80250 mg 100250 mg For the administration of such dosages, it is envisaged that more than one capsule or other dosage unit form will in practice conveniently be used to make up a single dosage. Thus for example administration of two capsules as described in any of the following Examples 3 to 5 will provide over the minimum advantageous dosage of both active ingredients. If desired, more than two capsules or other dosage unit forms can be used to make up a single dosage. Also, for the purposes of long term treatment, somewhat lower dosages of the active ingredients may be preferred. Thus the compositions according to the invention may have the following active ingredient contents: Particularly Preferred Advantageous advantageous active active active ingredient ingredient ingredient content content content Dihomo-y-linolenic acid (or physiologically functional derivative thereof) 10250 mg 15-150 mg 20-150 mg y-Linolenic acid (or physiologically functional derivative thereof) 15-500 mg 20-250 mg 25-250 mg The compositions according to the invention may be used in a method for the treatment or prophylaxis of venous and arterial thrombosis which comprises administering a dosage of from 15 to 500 mg, advantageously from 20 to 250 mg and with particular advantage from 25 to 250 mg of y-linolenic acid or physiologically functional derivative thereof together with a dosage of from 10 to 250 mg, advantageously from 15 to 150 mg and with particular advantage from 20 to 150 mg of dihomo-y-linolenic acid or physiologically functional derivative thereof. The dosage is preferably administered daily and can with advantage be administered for a prolonged period of time.

As indicated above, when treating thrombotic conditions in fhe short term, somewhat higher quantities of the active ingredients are preferred. Thus, dihomoy-linolenic acid or physiologically functional derivative thereof may be conveniently administered in a dosage of from 40 to 250 mg, desirably from 60 to 150 mg and preferably from 80 to 150 mg, together with y-linolenic acid or functional derivative thereof conveniently in a dosage of from 60 to 500 mg, desirably from 80 to 250 mg and preferably from 100 to 250 mg.

The invention is further illustrated by the following Examples which are not intended to limit the invention in any manner.

EXAMPLES Pharmaceutical compositions containing a unit dose of the oil extract from the seeds of Oenothera biennis, L. with methyl dihomo-y-linolenate added are prepared by encapsulation of the natural oil in soft gelatin capsules manufactured by known methods.

The oil is extracted from the seeds by one of the conventional methods of extraction such as cold pressure, screw pressure after partially cooking the seed or solvent extract [see J. Chem. Soc., 1961, 2728].

Oil extracts from these seeds generally contain from 7-26% y-linolenic acid and from 7072 /" linoleic acid predominantly in the form of the triglyceride esters. Typical analytical results are as follows: Specific gravity 0.923 Iodine value 154 Ester value 191 Non-saponfiable matter 1.52 /" Acid value 1.4 Fractionation shows a yield of 97.0% of fatty acids in the form of methyl esters.

Proportions of methyl esters: Palmitate 6.14% Stearate 1.58% Oleate 10.15% Linoleate 72.60 /" y-Linolenate 8.87% If the y-linolenic and linoleic acid contents are below the desired levels, they are adjusted by adding the required quantities from a reserve stock of the acids obtained from previous seed stocks giving higher yields, or from concentrates of the acids in the form of the methyl or ethyl esters extracted from previous batches of oil, or produced by chemical synthesis.

A suitable preservative such as s4-tocopherol is added to the oil in a concentration of 0.1%.

Gelatin capsules containing oil extracts prepared as described above and having the following contents of active ingredients are prepared: Example 1 Active ingredient Content per capsule y-linolenic acid (triglyceride) 45 mg Dihomo-y-linolenic acid (methyl ester) 10 mg Example 2 Active ingredient Content per capsule y-linolenic acid (triglyceride) 45 mg Dihomo-y-linolenic acid (methyl ester) 20 mg Example 3 Active ingredient Content per capsule y-linolenic acid (triglyceride) 45 mg Dihomo-y-linolenic acid (methyl ester) 30 mg Example 4 Active ingredient Content per capsule y-linolenic acid (triglyceride) 45 mg Dihomo-y-linolenic acid (methyl ester) 40 mg Example 5 Active ingredient Content per capsule y-linolenic acid (triglyceride) 45 mg Dihomo-y-linolenic acid (methyl ester) 50 mg WHAT WE CLAIM IS: 1. A pharmaceutical composition for use as an antithrombotic agent which comprises effective amounts of a) y-linolenic acid or a physiologically functional derivative thereof, and b) dihomo-y-linolenic acid or a physiologically functional derivative thereof.

2. A composition as claimed in claim 1 wherein the y-linolenic acid and/or dihomo-y-linolenic acid are in the form of their C1~4 esters or glycerides.

3. A composition as claimed in claim 2 wherein the y-linolenic acid and/or dihomo-y-linolenic acid are in the form of their methyl or ethyl esters.

4. A composition as claimed in any of the preceding claims wherein the acids or derivatives thereof are in association with a pharmaceutical vehicle (as herein defined).

5. A composition as claimed in any of the preceding claims wherein the ylinolenic acid is in the form of an oil having a high y-linolenic acid content.

**WARNING** end of DESC field may overlap start of CLMS **.

Claims (18)

  1. **WARNING** start of CLMS field may overlap end of DESC **.
    Specific gravity 0.923 Iodine value 154 Ester value 191 Non-saponfiable matter 1.52 /" Acid value 1.4 Fractionation shows a yield of 97.0% of fatty acids in the form of methyl esters.
    Proportions of methyl esters: Palmitate 6.14% Stearate 1.58% Oleate 10.15% Linoleate 72.60 /" y-Linolenate 8.87% If the y-linolenic and linoleic acid contents are below the desired levels, they are adjusted by adding the required quantities from a reserve stock of the acids obtained from previous seed stocks giving higher yields, or from concentrates of the acids in the form of the methyl or ethyl esters extracted from previous batches of oil, or produced by chemical synthesis.
    A suitable preservative such as s4-tocopherol is added to the oil in a concentration of 0.1%.
    Gelatin capsules containing oil extracts prepared as described above and having the following contents of active ingredients are prepared: Example 1 Active ingredient Content per capsule y-linolenic acid (triglyceride) 45 mg Dihomo-y-linolenic acid (methyl ester) 10 mg Example 2 Active ingredient Content per capsule y-linolenic acid (triglyceride) 45 mg Dihomo-y-linolenic acid (methyl ester) 20 mg Example 3 Active ingredient Content per capsule y-linolenic acid (triglyceride) 45 mg Dihomo-y-linolenic acid (methyl ester) 30 mg Example 4 Active ingredient Content per capsule y-linolenic acid (triglyceride) 45 mg Dihomo-y-linolenic acid (methyl ester) 40 mg Example 5 Active ingredient Content per capsule y-linolenic acid (triglyceride) 45 mg Dihomo-y-linolenic acid (methyl ester) 50 mg WHAT WE CLAIM IS: 1. A pharmaceutical composition for use as an antithrombotic agent which comprises effective amounts of a) y-linolenic acid or a physiologically functional derivative thereof, and b) dihomo-y-linolenic acid or a physiologically functional derivative thereof.
  2. 2. A composition as claimed in claim 1 wherein the y-linolenic acid and/or dihomo-y-linolenic acid are in the form of their C1~4 esters or glycerides.
  3. 3. A composition as claimed in claim 2 wherein the y-linolenic acid and/or dihomo-y-linolenic acid are in the form of their methyl or ethyl esters.
  4. 4. A composition as claimed in any of the preceding claims wherein the acids or derivatives thereof are in association with a pharmaceutical vehicle (as herein defined).
  5. 5. A composition as claimed in any of the preceding claims wherein the ylinolenic acid is in the form of an oil having a high y-linolenic acid content.
  6. 6. A composition as claimed in claim 5 wherein the oil is obtained from
    Oenothera biennis L. or Borago officinalis.
  7. 7. A composition as claimed in either of claims 5 and 6 wherein the oil is fractionated and the fatty acid fraction containing triglycerides of y-linolenic acid and linoleic acid is used.
  8. 8. A composition as claimed in any of the preceding claims in a form suitable for oral, parenteral, rectal or topical administration.
  9. 9. A composition as claimed in claim 8 wherein the composition is in the form of a tablet, coated tablet, capsule, cachet, powder, granulate, syrup, elixir, injection solution, suspension, suppository, cream or lotion.
  10. 10. A composition as claimed in any of the preceding claims in the form of dosage units.
  11. 11. A composition as claimed in claim 10 wherein each dosage unit for oral administration comprises from 40 mg to 250 mg of dihomo-y-linolenic acid or physiologically functional derivative thereof and from 60 to 500 mg of y-linolenic acid or physiologically functional derivative thereof.
  12. 12.A composition as claimed in claim 11 wherein each dosage unit for oral administration comprises from 60 to 150 mg of dihomo-y-linolenic acid or physiologically functional derivative thereof and from 80 to 250 mg of linolenic acid or physiologically functional derivative thereof.
  13. 13. A composition as claimed in claim 12 wherein each dosage unit for oral administration comprises from 80 to 150 mg of dihomo-y-linolenic acid or physiologically functional derivative thereof and from 100 to 250 mg of y-linolenic acid or physiologically functional derivative thereof.
  14. 14. A composition as claimed in claim 10 wherein each dosage unit for oral administration comprises from 10 to 250 mg of dihomo-y-linolenic acid or physiologically functional derivative thereof and from 15 to 500 mg of y-linolenic acid or physiologically functional derivative thereof.
  15. 15. A composition as claimed in claim 14 wherein each dosage upit comprises from 15 to 150 mg of dihomo-y-linolenic acid or physiologically functional derivative thereof and from 20 to 250 mg of y-linolenic acid or physiologically functional derivative thereof.
  16. 16. A composition as claimed in claim 15 wherein each dosage unit comprises from 20 to 150 mg of dihomo-y-linolenic acid or physiologically functional derivative thereof and from 25 to 250 mg of y-linolenic acid or physiologically functional derivative thereof.
  17. 17. A pharmaceutical composition as claimed in claim 1 substantially as herein described.
  18. 18. A pharmaceutical composition for use as an antithrombotic agent which comprises effective amounts of y-linolenic acid or a physiologically functional derivative thereof, and dihomo-y-linolenic acid or a physiologically functional derivative thereof substantially as herein described with reference to the Examples.
GB214577A 1976-11-04 1977-01-19 Pharmaceutical compositions Expired GB1580444A (en)

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GB4600276 1976-11-04
GB214577A GB1580444A (en) 1976-11-04 1977-01-19 Pharmaceutical compositions

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GB214577A GB1580444A (en) 1976-11-04 1977-01-19 Pharmaceutical compositions
DE19772749492 DE2749492C2 (en) 1976-11-04 1977-11-04

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EP0035856A2 (en) * 1980-03-07 1981-09-16 Efamol Limited Pharmaceutical and dietary compositions
EP0090378A1 (en) * 1982-03-26 1983-10-05 Eisai Co., Ltd. Isoprenylcarboxylic acid-containing composition for external use
WO1988002221A1 (en) * 1986-09-29 1988-04-07 Kabivitrum Ab A granulate containing gamma linolenic acid, eicosapentaenoic acid and/or docosahexaenoic acid, the method for its manufacturing, its use in edible products, and a tablet containing it
FR2633926A1 (en) * 1988-07-06 1990-01-12 Azar Roger Novel esters of fatty acid, methods of obtaining them and industrial jobs
US5196198A (en) * 1989-06-02 1993-03-23 Abbott Laboratories Parenteral nutrition product
US5847000A (en) * 1994-03-01 1998-12-08 Scotia Holdings Plc Fatty acid derivatives

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AU527784B2 (en) * 1978-05-26 1983-03-24 Bang, Hans Olaf Dr. Treatment of thromboembolic conditions withall-z)-5, 8, 11, 14, 17-eicosapentaenoic acid
USRE31836E (en) * 1979-05-18 1985-02-19 Efamol Limited Pharmaceutical and dietary composition
IE49783B1 (en) * 1979-05-18 1985-12-11 Efamol Ltd Pharmaceutical and dietary composition comprising epsilon-linolenic acids
FR2490631B1 (en) * 1980-09-24 1983-11-18 Roussel Uclaf
FR2548021B1 (en) * 1983-06-29 1986-02-28 Dick P R Prolonged and continuous dermal pharmaceutical compositions based on essential fatty acids
GB8319073D0 (en) * 1983-07-14 1983-08-17 Efamol Ltd Fatty acid compositions
FR2574089B1 (en) * 1984-12-03 1987-04-10 Inst Nat Sante Rech Med Process for the production of fatty acids, in particular g-linoleic acid from tetrahymena, products obtained and medicinal or food preparation containing g-linolenic acid or derivatives thereof as anti-aggregation agent
GB8507058D0 (en) * 1985-03-19 1985-04-24 Efamol Ltd Pharmaceutical & dietary compositions
GB8524275D0 (en) * 1985-10-02 1985-11-06 Efamol Ltd Pharmaceutical & dietary compositions
FR2617161B1 (en) * 1987-06-29 1989-10-27 Azar Robert Novel unsaturated fatty acid glycerides and process for obtaining same
AU629286B2 (en) * 1988-12-23 1992-10-01 Arthur George Bolt Anti-inflammatory liniment
EP0400547A1 (en) * 1989-06-02 1990-12-05 Abbott Laboratories Parenteral nutrition product
GB9125602D0 (en) * 1991-12-02 1992-01-29 Efamol Holdings Method of preventing reocclusion of arteries
DE102005058369A1 (en) * 2005-12-06 2007-06-14 Lts Lohmann Therapie-Systeme Ag Unsaturated fatty acids as thrombin inhibitors

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0035856A2 (en) * 1980-03-07 1981-09-16 Efamol Limited Pharmaceutical and dietary compositions
EP0035856A3 (en) * 1980-03-07 1981-09-23 Efamol Limited Pharmaceutical and dietary compositions
EP0090378A1 (en) * 1982-03-26 1983-10-05 Eisai Co., Ltd. Isoprenylcarboxylic acid-containing composition for external use
WO1988002221A1 (en) * 1986-09-29 1988-04-07 Kabivitrum Ab A granulate containing gamma linolenic acid, eicosapentaenoic acid and/or docosahexaenoic acid, the method for its manufacturing, its use in edible products, and a tablet containing it
EP0266323A1 (en) * 1986-09-29 1988-05-04 KabiVitrum AB Tablet containing gamma-linolenic acid, eicosa pentaenoic acid and/or docosahexaenoic acid, and method for its manufacturing
FR2633926A1 (en) * 1988-07-06 1990-01-12 Azar Roger Novel esters of fatty acid, methods of obtaining them and industrial jobs
EP0356270A2 (en) * 1988-07-06 1990-02-28 Roger F. Azar Fatty-acid esters, method for their preparation and their industrial use
EP0356270A3 (en) * 1988-07-06 1990-07-11 Roger F. Azar Fatty-acid esters, method for their preparation and their industrial use
US5196198A (en) * 1989-06-02 1993-03-23 Abbott Laboratories Parenteral nutrition product
US5847000A (en) * 1994-03-01 1998-12-08 Scotia Holdings Plc Fatty acid derivatives
US6177470B1 (en) 1994-03-01 2001-01-23 Scotia Holdings Plc Methods of treatment using ascorbyl gamma linolenic acid or ascorbyl dihomo-gamma-linolenic acid

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DE2749492C2 (en) 1982-11-04

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