WO1997006812A1

WO1997006812A1 - Herbal pharmaceutical composition

Info

Publication number: WO1997006812A1
Application number: PCT/AU1995/000495
Authority: WO
Inventors: William Flynn; David Sung Hwan Ahn
Original assignee: Sci-Quip Austasia Pty. Ltd.
Priority date: 1995-08-15
Filing date: 1995-08-15
Publication date: 1997-02-27
Also published as: AU3157595A

Abstract

The present invention relates to a pharmaceutical or veterinary composition comprising pharmaceutically or veterinarily effective amounts of extracts from at least one plant selected from each of the Papaveraceae family, the Umbelliferae family and the Leguminosae family and its use in the treatment and/or prophylaxis of pain.

Description

HERBAL PHARMACEUTICAL COMPOSITION

The present invention relates to a pharmaceutical composition containing herbal ingredients and its use in therapy, particularly for the treatment and/or prophylaxis of pain. Aspirin, indomethecin, codeine and naproxen are representative examples of analgesic drugs which may be used to relieve pain. Many analgesic drugs also have marked anti-inflammatory actions. Some of these drugs are known to cause gastric irritation at doses required to produce analgesic and/or anti-inflammatory effects. Gastric irritation may result in symptoms of upper gastro-intestinal discomfort, acute gastric erosion and aggravation of chronic peptic ulceration. Although these problems only occur in a minority of patients, an increased loss of blood in the faeces is observed in the remaining patients which do not necessarily develop gastric irritation.

There is a need for a natural product as opposed to a chemically produced product for the relief of pain.

According to one aspect of the present invention there is provided a pharmaceutical or veterinary composition comprising pharmaceutically or veterinarily effective amounts of extracts from at least one plant selected from each of the Papaveraceae family, the Umbelliferae family and the Leguminosae family.

The present invention also provides a pharmaceutical or veterinary composition as defined above for use in therapy including the treatment and/or prophylaxis of pain. According to another aspect of the present invention there is provided a method for the treatment and/or prophylaxis of pain which comprises administering a therapeutically effective amount of the pharmaceutical or veterinary composition defined above to a subject in need thereof.

According to a further aspect of the present invention there is provided the use of a pharmaceutical or veterinary composition as defined above in the manufacture of a medicament for the treatment and/or prophylaxis of pain. The present invention still further provides a pharmaceutical or veterinary composition as defined above for use in the treatment and/or prophylaxis of pain.

The pain may result from various disorders, such as, musculo-skeletal pain, tension, sinusitis, menstrual pain, stomach pain, gout, neuritis, toothache, headache and migraine. The musculo-skeletal pain may include arthritis, myalgia, lumbego, sciatica and fibrositis.

Thus, the present invention also extends to a method for the treatment and/or prophylaxis of musculo-skeletal pain, tension, sinusitis, menstrual pain, stomach pain, gout, neuritis, toothache, headache and migraine which comprises administering a therapeutically effective amount of the pharmaceutical or veterinary composition defined above to a subject in need thereof.

The extracts are conveniently isolatable from the leaves, bark, stems, flowers and/or roots of the plant. Generally, the plant material is ground to a powder using any suitable apparatus, such as, a grinder. Extracts are then prepared of the ground plant material.

The plant extract obtained from the Papaveraceae family is preferably selected from the genus Corydalis, more preferably from the species Corydalis ambigua. The main constituents of Papaveraceae Corydalis are benzoquinolizines, more specifically corydaline, tetrahydrocolumbamine, protopine, tetrahydropalmatine, corydalmine, corybulbine, dehydrocorydaline chloride, dehydrocorydaline nitrate, dehydrocorydaline bromide, columbamine nitrate and coptisine nitrate. The chemical structures some of these main constituents are shown in Formulae (I) and (II):

The plant extract obtained from the Umbelliferae family is preferably selected from the genus Angelica, more preferably from the species Angelica dahurica. The main constituents of Umbelliferae Angelica are shown in Formulae (III) to (IX):

The plant extract obtained from the Leguminosae family is preferably selected from the genus Glycyrrhiza more preferably from the species Glycyrrhiza glabra which is commonly known as liquorice.

Thus, in a preferred embodiment the present invention provides a pharmaceutical or veterinary composition comprising pharmaceutically or veterinary effective amounts of liquorice and extracts from at least one plant selected from each of Corydalis ambigua and Angelica dahurica.

The composition may also contain extracts from at least one plant selected from each of the Liliaceae family and the Paeoniaceae family. The plant extract obtained from the Liliaceae family is preferably selected from the genus Anemarrhena, more preferably from the species Anemarrhena asphodeloides.

Preferably, the plant extract obtained from the Paeoniaceae family is selected from the genus Paeonia, more preferably from the species Paeonia lactiflora.

Thus, according to another preferred embodiment the present invention provides a pharmaceutical or veterinary composition comprising pharmaceutically or veterinarily effective amounts of extracts from at least one plant selected from each of the Papveraceae family, the Umbelliferae family, Leguminosae family, the Liliaceae family and the Paeoniaceae family.

In a particularly preferred embodiment, the present invention provides a pharmaceutical or veterinary composition comprising pharmaceutically or veterinarily effective amounts of liquorice and extracts from at least one plant selected from each of Corydalis ambigua, Angelica daturica, Anemarrhena asphodeloides and Paeonia lactiflora.

The subject may be a human or an animal such as a domestic or wild animal, particularly an animal of economic importance.

An "effective amount" of the pharmaceutical or veterinary composition is an amount sufficient to relieve pain. While it is possible for the pharmaceutical or veterinary composition to be administered alone, it is preferable that it is administered with one or more pharmaceutically or veterinarily acceptable carrier, adjuvants, diluent and/or excipients.

Accordingly, the present invention also relates to a pharmaceutical or veterinary composition which comprises pharmaceutically or veterinarily effective amounts of extracts from at least one plant selected from each of the Papveraceae family, the

Umbelliferae family and the Leguminosae family in association with a pharmaceutically or veterinarily acceptable carrier, diluent, adjuvant and/or excipient. As discussed above, this composition may also contain extracts from at least one plant selected from each of the Liliaceae family and the Paeoniaceae family.

The composition of the invention may be advantageously used in therapy in combination with other medicaments, such as, for example, other analgesic and/or anti-inflammatory drugs which are also preferably natural products. Hence a preferred method in accordance with the present invention utilises the composition of the invention in conjunction with another medicament. For ease of reference the plant extracts contained in the composition of the invention will hereinafter be referred to as the "active ingredients".

The composition of the invention may be administered for therapy by any suitable route, including oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intrasternal and intradermal). Preferably, administration will be by the oral route, however it will be appreciated that the preferred route will vary with the condition and age of the subject. The carrier, diluent, adjuvant and/or excipient must be pharmaceutically or veterinary "acceptable" in the sense of being compatible with the other ingredients of the composition and not injurious to the subject. Compositions include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. The compositions may conveniently be presented in unit dosage form and may be prepared by methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, diluents, adjuvants and/or excipients or finely divided solid carriers or both, and then if necessary shaping the product.

Compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, sachets or tablets each containing a predetermined amount of the active ingredients; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The composition may also be presented as a bolus, electuary or paste.

A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g inert), diluent, preservative, disintegrant (e.g. sodium starch glycollate, povidone, cross-linked povidone or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, microcrystalline cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach. Compositions suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavoured basis, usually sucrose and acacia or tragacanth gum; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin or sucrose and acacia gum; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

For topical application for the skin, the active ingredient may be in the form of a cream, ointment, jelly, solution or suspension.

For topical application to the eye, the active ingredient may be in the form of a solution or suspension in a suitable sterile aqueous or non-aqueous vehicle. Additives, for instance buffers, preservatives including bactericidal and fungicidal agents, such as phenyl mercuric acetate or nitrate, benzalkonium chloride or chlorohexidine and thickening agents such as hypromellose may also be included. Compositions for rectal administration may be presented as a suppository with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the active ingredient. Such excipients include cocoa butter or a salicylate.

Compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate. Compositions suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the composition isotonic with the blood of the intended subject; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The compositions may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

Preferred unit dosage compositions are those containing a daily dose or unit, daily sub-dose, as hereinabove described, or an appropriate fraction thereof, of an active ingredient. The active ingredients may also be presented for use in the form of veterinary compositions, which may be prepared, for example, by methods that are conventional in the art. Examples of such veterinary compositions include those adapted for:

(a) oral administration, external application, for example drenches (e.g.

aqueous or non-aqueous solutions or suspensions); tablets or boluses; powders, granules or pellets for admixture with feed stuffs; pastes for application to the tongue;

(b) parenteral administration for example by subcutaneous,

intramuscular or intravenous injection, e.g. as a sterile solution or suspension; or (when appropriate) by intramammary injection where a suspension or solution is introduced into the udder via the teat;

(c) topical application, e.g. as a cream, ointment or spray applied to the skin; or

(d) intravaginally, e.g. as a pessary, cream or foam.

It should be understood that in addition to the ingredients particularly mentioned above, the compositions of this invention may include other agents conventional in the art having regard to the type of composition in question, for example, those suitable for oral administration may include such further agents as binders, sweeteners, thickeners, flavouring agents, disintegrating agents, coating agents, preservatives, lubricants and/or time delay agents.

Suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharin. Suitable disintegrating agents include corn starch, methylcellulose, polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid or agar. Suitable flavouring agents include peppermint oil, oil of wintergreen, cherry, orange or raspberry flavouring. Suitable coating agents include polymers or copolymers of acrylic acid and/or methacrylic acid and/or their esters, waxes, fatty alcohols, zein, shellac or gluten. Suitable preservatives include sodium benzoate, vitamin E, alpha-tocopherol, ascorbic acid, methyl paraben, propyl paraben or sodium bisulphite. Suitable lubricants include magnesium stearate, steric acid, sodium oleate, sodium chloride or talc. Suitable time delay agents include glyceryl monostearate or glyceryl distearate.

Preferably the pharmaceutically or veterinarily acceptable carrier, diluent, adjuvant and/or excipient is calcium sulphate; a binding agent, such as, calcium hydrogen phosphate; a controlled release agent, such as, microcrystalline cellulose; a disintegrant, such as, povidone and cross-linked povidone; a lubricant such as, magnesium stearate; a thickening agent, such as, hypromellose; and a coating agent, such as, propylene glycol.

In another preferred embodiment there is provided a pharmaceutical or veterinary composition which comprises pharmaceutically or veterinarily effective amounts of liquorice and calcium sulphate and extracts from at least one plant selected from each of Corydalis ambigua and Angelica dahurica. This composition is particularly useful in the form of a capsule.

An alternative embodiment provides a pharmaceutical or veterinary composition which comprises pharmaceutically or veterinarily effect amounts of liquorice, calcium sulphate, calcium hydrogen phosphate, povidone, cross-linked povidone, microcrystalline cellulose, magnesium stearate, hypromellose and propylene glycol and extracts from at least one plant selected from each of Corydalis ambigua, Angelica dahurica, Paeonia lactiflora and Anemarrhena asphodeloides. This composition is useful in the form of a tablet.

The composition of the invention may also conveniently be in the form of a kit in which the active ingredients are held separately for separate, sequential or simultaneous use.

The desired dose is preferably presented as two, three, four, five, six or more sub-doses administered at appropriate levels throughout the day, generally once every 3 to 4 hours. These sub-doses may be administered in unit dosage forms. The amounts of active ingredients present in the preferred capsule composition are generally in the range of about 30% Corydalis ambigua extract, 30% Angelica dahurica extract, 10% liquorice and the balance of 30% being one or more pharmaceutically or veterinarily acceptable carriers, diluents, adjuvants and/or excipients, preferably calcium sulphate.

The invention will now be described with reference to the following Examples. These Examples are not to be construed as limiting the invention in any way. EXAMPLE 1 - CAPSULE COMPOSITION

The composition of the capsules was as follows:

The capsules were prepared by mixing the powdered roots with the calcium sulphate dihydrate and inserting the mixture into a hard gelatin capsule.

EXAMPLE 2 - SPECIFICATIONS FOR ACTIVE INGREDIENTS (i) Powdered Corydalis ambigua root

Test 1 - Chemical test

2 g of powdered sample was mixed with 0.5N sulphuric acid. The mixture was shaken and then filtered. 0.4 ml of 1% potassium ferricyanide and 0.3 ml of 1% ferric chloride were added to the filtrate to form a blue precipitate. The mixture was filtered and 2 ml of 7.5% potassium dichromate was added to the filtrate to form a yellow precipitate.

Test 2 - Thin Layer Chromatography

Alcoholic ammonia solution (1:1) was added to 5 g of powdered sample to form a slurry. The slurry was extracted with benzene by warming the mixture on a water bath. The mixture was cooled and filtered. The benzene filtrate was extracted with 20% hydrochloric acid. The aqueous fraction was separated, treated with ammonia solution to alkaline pH and extracted with chloroform. The chloroform extract was separated and then dried over anhydrous sodium sulphate. The extract was evaporated to dryness. The extract and reference material were applied to the TLC plate. The TLC plate used was silica gel G which was developed using benzene : alcohol 95% (4:1). Spots were visualised under UV light and those of the extract corresponded with those of the reference in Rf value.

Test 1 - Fluorescence test

Powdered angelica was mixed with water and shaken. The suspension was filtered and the filtrate examined under a UV lamp. A blue fluorescence was observed. Test 2 - Colour reaction

A small sample of powder was extracted with ether by shaking for 5 mins and allowing the mixture to stand for a further 20 mins. 2-3 drops of hydroxylamine hydrochloride in methanol and 2-3 drops of 20% potassium hydroxide in methanol were added to 1 ml of the extract. The mixture was warmed in a water bath. After cooling, the pH was adjusted to 3-4 using dilute hydrochloric acid. The solution turned purple-red on the addition of 1-2 drops 1% ferric chloride solution.

Test 3 - Thin layer Chromatography

An ether extract of the reference material was prepared as described in Test 2 above. The ether extracts from the test and reference material were spotted onto the TLC plates and developed as described below.

I - Alumina G

chloroform:butyl ether:ethyl acetate

1 : 22 3

II - Silica gel G

toluene:ethyl formate:formic acid

5 : 4 : 1

The plates were dried and examined under UV light. I - two blue fluorescent spots at Rf 0.6 and 0.5 two yellow fluorescent spots at Rf 0.4 and 0.33

II - two fluorescent spots at Rf 0.42 and 0.59 EXAMPLE 3 - CAPSULE COMPOSITION SPECIFICATIONS

As the herbs contain a mixture of substances which are related by class, for the purposes of labelling, these having been quantitated in terms of representative members of those classes of compounds. In the case of Angelica dahurica root, the benzopyrone class of compounds is quantitated as 7-methoxycourmarin which is representative of the major components. The mixture of dibenzoquinolizine alkaloids from Corydalis ambigua root are quantitated as tetrahydropalmatine, which is a member of this class.

Test 1 - Fluorescence test

The contents of two capsules were mixed with water and shaken. The suspension was filtered and the filtrate examined under UV light. A blue fluorescence was observed.

Test 2 - Chemical test

10 g of powdered sample was mixed with 0.5N sulphuric acid. The mixture was shaken and then filtered. 0.4 ml of 1% potassium ferricyanide and 0.3 ml of 1% ferric chloride was added to 2 ml of the filtrate. A blue precipitate formed. The mixture was filtered and 2 ml of 7.5% potassium dichromate was added to the filtrate. A yellow precipitate formed.

EXAMPLE 5 - CLINICAL TEST RESULTS

Selection of Patients

Males and females, 18 years or older, with symptomatic musculo-skeletal pain (osteoarthritis, fibrositis, sciatica or whiplash injury of the neck) were accepted into the study.

Patients who needed to take oral medication for pain relief were excluded from the study. Drugs, Dosage and Study

Patients were given the composition described in Example 1 above or placebo for three weeks and vice versa for the next three weeks. Patients were asked to tabulate their symptomatic response throughout the period.

At the onset of pain, the patients were instructed in take 1 capsule and repeat after no response in ½ hour with the maximum of 4 capsules per day.

No other analgesic drugs were allowed to be administered for the period of the study.

Conduct of the Study

Patients were interviewed at the beginning, after three weeks and at the end of the study.

Results

This study was designed to evaluate the efficacy of the composition against the placebo in musculo-skeletal discomfort and pain.

Demographic data for all patients appear in Table 1 below.

A physician's assessment of the overall response is presented in Table 2 below.

Side-effects

One patient complained of difficulty swallowing the capsules and one patient complained of slight nausea after taking the capsules, but no patient discontinued the study due to side effects. Discussion

The parameters used for measuring response are generally subjective e.g. pain scale and global response scale, or semi-objective e.g. return to active activity or work. Conclusion

The study in nine patients clearly demonstrates that the composition is effective in the relief of discomfort and pain in musculo-skeletal disorders when compared with the placebo. EXAMPLE 6 - STUDY OF THE EFFICACY OF THE COMPOSITION FOR

PAIN RELIEF

Pain assessment

Pain relief was assessed on a scale of 0-5 by subjective sense of pain relief on a daily basis. Monitoring was by the patients and the results tabulated at the regular follow-ups.

Effect on the pain response expected from the steroid injections

Intra-articular injections of steroid was composed of 1 ml of depemedrol mixed with 0.75 ml of 1% xylocaine.

Depomedrol injection is painful and xylocaine is added to reduce this. However, the anaesthetic effect of the xylocaine is only temporary and lasts up to 4 to 6 hours. Depomedrol injections may be painful up to 2 to 3 days on the average. The anti-inflammatory effects of the steroid usually start after 2 to 4 days on the average and may continue to give relief for up to 4 to 6 weeks.

For those patients receiving intra-articular injections, the response to the analgesic effects of the composition or placebo was noted mainly for the post-injection period when the effect of xylocaine had worn off.

The detailed analysis of the individual subjective response is shown in Table 3 below.

EXAMPLE 7 - TABLET COMPOSITION

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

Claims

CLAIMS:

1. A pharmaceutical or veterinary composition comprising pharmaceutically or veterinarily effective amounts of extracts from at least one plant selected from each of the Papaveraceae family, the Umbelliferae family and the Leguminosae family.

2. A composition according to Claim 1, wherein the plant extract obtained from the Papaveraceae family is selected from the genus Corydalis.

3. A composition according to Claim 1 or Claim 2, wherein the plant extract obtained from the Papaveraceae family is selected from Corydalis ambigua.

4. A composition according to any one of the preceding claims, wherein the plant extract obtained from the Umbelliferae family is selected from the genus Angelica.

5. A composition according to any one of the preceding claims, wherein the plant extract obtained from the Umbelliferae family is selected from the species Angelica dahurica.

6. A composition according to any one of the preceding claims, wherein the plant extract obtained from the Leguminosae family is selected from the genus Glycyrrhiza.

7. A composition according to any one of the preceding claims, wherein the plant extract obtained from the Leguminosae family is selected from the species Glycyrrhiza glabra.

8. A composition according to any one of the preceding claims, wherein the plant extract obtained from the Leguminosae family is liquorice.

9. A composition according to any one of the preceding claims, which further comprises extracts from at least one plant selected from each of the Liliaceae family and the Paeoniaceae family.

10. A composition according to Claim 9, wherein the plant extract obtained from the Liliaceae family is selected from the genus Anemarrhena.

11. A composition according to Claim 9 or Claim 10, wherein the plant extract obtained from the Liliaceae family is selected from the species Anemarrhena asphodeloides.

12. A composition according to Claims 9 to 11, wherein the plant extract obtained from the Paeoniaceae family is selected from the genus Paeonia.

13. A composition according to Claims 9 to 12, wherein the plant extract obtained from the Paeoniaceae family is selected from the species Paeonia lactiflora.

14. A composition according to any one of the preceding claims, which further comprises one or more pharmaceutically or veterinarily acceptable carriers, adjuvants, diluent and/or excipients.

15. A composition according to Claim 14, wherein the pharmaceutically or veterinarily acceptable carrier, adjuvant, diluent and/or excipient is calcium sulphate, a binding agent, controlled release agent, disintegrant, lubricant, thickening agent and/or coating agent.

16. A composition according to Claim 15, wherein the binding agent is calcium hydrogen phosphate.

17. A composition according to Claim 15 or Claim 16, wherein the controlled release agent is microcrystalline cellulose.

18. A composition according to any one of Claims 15 to 17, wherein the disintegrant is povidone or cross-linked povidone.

19. A composition according to any one of Claims 15 to 18, wherein the lubricant is magnesium stearate.

20. A composition according to any one of Claims 15 to 19, wherein the thickening agent is hypromellose.

21. A composition according to any one of Claims 15 to 20, wherein the coating agent is propylene glycol.

22. A composition according to any one of the preceding claims, which is in a form suitable for oral administration.

23. A composition according to Claim 16 wherein the composition is in the form of a tablet or capsule.

24. A method for the treatment and/or prophylaxis of pain which comprises administering a therapeutically effective amount of the pharmaceutical or veterinary composition according to any one of the preceding claims to a subject in need thereof.

25. A method according to Claim 24, wherein the pain results from musculo-skeletal pain, tension, sinusitis, menstrual pain, stomach pain, gout, neuritis, toothache, headache and/or migraine.

26. A method according to Claim 25, wherein the musculo-skeletal pain is arthritis, myalgia, lumbego, sciatica and/or fibrositis.

27. Use of a pharmaceutical or veterinary composition according to any one of Claims 1 to 23 in the manufacture of a medicament for the treatment and/or prophylaxis of pain.

28. A pharmaceutical or veterinary composition according to any one of Claims 1 to 23 for use in the treatment and/or prophylaxis of pain.