WO2002085394A1

WO2002085394A1 - The process of preparing the topical anti-inflammatory/analgesic preparation

Info

Publication number: WO2002085394A1
Application number: PCT/IB2002/001306
Authority: WO
Inventors: Bakulesh Mafatlal Khamar; Vandana Dasharathbhai Mody; Kalpesh Karunashankar Pandya
Original assignee: Bakulesh Mafatlal Khamar; Vandana Dasharathbhai Mody; Kalpesh Karunashankar Pandya
Priority date: 2001-04-24
Filing date: 2002-04-19
Publication date: 2002-10-31

Abstract

The present invention provides the process of preparing the topical anti-inflammatory and analgesic preparation comprising herbal ingredients. The process involves the extraction of herbal ingredients in the solvent; concentrating; filtration of solvent; addition of base oil; removel of solvent by boiling the mixture; resultant extract is allowed to cool; and addition of volatile oils. The process for preparation of compositions comprises of the extratction of invidual herb or a mixture thereof. Cissus quadragularis (Asthisamhara) and Costus specious (Bramhatirtha) are the essential herbs to provide synergistic compositions. The other herbal ingredients used optionally in the process are Terminalia chebula (Haritaki), Terminali bellerica (Bibhitaka), Emblica officinalis (Amalaki), Melia azadirchta (Nimba), Vitex negundo (Nirgundi), Commiphora mukul (Guggulu). The volatile oils used optinally in the process are Pinus longifolia (Sarala), Camphora officinarum (karpur), Apium graveolens (Ajmoda), Cedrus deodara (Devdaru oil), Eucalyptus globulus (Nilgiri oil), Melaleuca leucadendron (cajuput oil). The compositions derived from the process are found to be effective in relieving various painful and inflammatory conditions.

Description

THE PROCESS OF PREPARING THE TOPICAL ANTI-INFLAMMATORY/ ANALGESIC PREPARATION

This invention relates to the process of preparing the topical anti-inflammatory/ analgesic preparation.

BACKGROUND AND PRIOR ART RELATING TO THE INVENTION:

Plants and herbs have long been used for medicinal purposes. Indeed, India has been known since long of the healing powers of certain herbs as remedies for various illnesses. The present invention provides the process of preparing the topical anti- inflammatory preparation for the use in the treatment of inflammatory conditions of rheumatoid arthritis, ^' osteoarthritis, cervical and ankylosing spondylitis, and painful conditions of frozen shoulder, stiff neck, back aches and musculoskeletal disorders.

Typically, herbal medicines are obtained as trie active compound(s) by extraction process from plant tissues. Natural ingredients? e.g., herbs, have also been used to treat bone and joint inflammation, especially in' India, and, increasingly, in western countries.

The Ayurvedic system of Indian traditional medicine provides many plants for the treatment of inflammatory disorders in human b'eings and animals. Majority of these plants have been investigated individually for their beneficial medicinal properties.

Commiphora mukul (Guggul): Commiphora mukul is grown in the arid and rocky zones in certain parts of Southwest and Northwestern region of India. The Oleoresin from commiphora mukul contains 0.37% essential oil containing mainly myrecene, dimyrecene, and polymyrecene. The steroidal component of petroleum ether extract of c. mukul has marked antiarthritic effect, comparable to that of hydrocortisone and more potent than phenylbutazone (1). It has a high anti-inflammatory potential against Brownlee's formaldehyde induced arthritis in albino rats (2). Carragenan oedema of the rat paw also regressed on exposure to the steroidal component of petroleum ether extract of C.mukul (3,4). The gum resin from C .mukul has been used in the treatment of various clinical types, of arthritis (5). The aqueous extract of C.mukul significantly inhibited maximum and total oedema response of carragenan-iήduced rat paw edema (6).

Vitex negundo (Nirgundi) : Vitex negundo is grown commonly in Wastelands, on the roadside, on the banks of streams or in moist places near decidous forests. The ethylacetate extract of leaves showed a significant activity against carragenan. 5-HT and bradykinin-induced inflammatory oedema. It also possessed significant inhibitory effect against granuloma pouch and cotton pellet implantation though less potent than phenylbutazone and beta-methasone(7,8). Patients with rheumatoid arthritis showed encouraging results when treated with decoctionl of nirgundi ρlant(9).

Cissus quadrangularis (Asthisamhara): The plant cissus quadrangularis is a creeper common in the hotter parts of India, used in folklore medicine to heal bone fractures. The effect of the plant on the healing of fractures has been extensively studied by Udupa and Prasad (10-13). The anabolic phytoste oid has been shown to markedly induce an early regeneration of the connective tissue and rapid mineralisation of callus. The extracts when administered either intra-muscularly or locally, reduces the healing time of fractures (14).

Costus speciosus (Bramhatirtha): The plant coshαs speciosus is distributed more or less throughout India. The root is pungent, 'bitter useful in inflammation and rheumatism (15).

Melia azadirachts (Nimba) : Melia a zadirachta jis a indigenous tree grown in all the plains in the Indian subcontinent. Seed oil and IKernel oil are useful in rheumatism and sprains when applied locally (16).

Emblica Officinalis (Amalakee) : Emblica officinalis grows throughout India upto 4500 ft². The water fraction of methanolic extracts of leaves of Emblica officinalis significantly inhibited the edema formation induced by carrageenin and dextran in rat hind paw. The anti-inflammatory mechanism off this extract is through its inhibitory action against the migration of polymorphonuclear leucocytes (17).

Terminalia chebula (Haritaki) : Terminalia chebύla grows below an elevation of 1000 m above sea level throughout India except in dryi and arid regions of Rajasthan.

Terminalia Belerica (Bibhitaka) : Terminalia Belerica grows throughout the forests of India, Burma, Srilanka except in the dried and arid regions.

Emblica officinalis, Terminalia chebula and Terminalia Belerica prevent aging and impart longevity, immunity, and enhance body resistance against disease (18).

Camphora officinarum (Karpura): Comphora o'fficinarum is commonly distributed throughout India, Japan and China. It can be used externally in the cases of inflammations, bruises and sprains.

Pinus longifolia (Sarala) : Pinus longifolia is found in Himalayas at altitude of 450- 2400 m. It grows well in the plains. It can be used as a rubificient in rheumatism and for deep-seated inflammation. .

The purpose of the present invention is to provide a process of preparing the topical formulation, which relieves inflammation and pain effectively at local site without producing any local irritation.

Several herbal topical preparations are available in India for the treatment of pain and inflammation, which are described as follows:

Rheuma oil from Baidyanath consisting decoction derived from Arun mookl, Dhatura panchang, Ashwagandha, Satavari, Amala, Haldi, Kuchala, Vastanabh prasarini each 3% w/v, kapur 5% w/v. Tarpio oil 10% w/v Gaηdh purna oil 25% v/v in Til oil base.

Rhumasy in the form of oil and ointment from jZandu consisting a preparation from Narayan oil 2.5 ml, Vishagarbha oil 2.5 ml, Mah'a Mash oil 2.5 ml, and Gandhpuro oil 2.5 ml. Rumalaya cream from Himalaya drug Co. consisting of oil of Karpoora 5%, Putiha 10%, Sarala 5%, Thwak 2.5%, Oil processed with Jatamansi, Kushtha, Jyotishmati, Nirgundi, Nishnu priya, Vacha, Yavani, Akarakarabha, Alarka, Dhatura, Rasna, Laksha, Maricha, Devdaru, Daruharidra, Ganiihaava hasta, Manjistha, Chitraka, Karavira, Dashamoola 22% in a cream base.

Rheumatil oil and gel from Dabar consisting ofjMahanarayan oil 70%, Gandhapuro oil 10%, Pudina satva 3%, Neelgiri oil 2%, Lava g oil 2%, Guggula satva 2%, Sunthi satva 1% in a oil or gel base.

Compositions composed of natural ingredients! and said to be useful in reducing inflammation are disclosed in several US patents, e.g., in U.S. Pat. Nos.5,120,538, 5,494,668, 5,683,698, 5,707,631, 5,916,565, ; 5,888,514, 5,908,628; 5,788,971; 5,854,291; and 5,910,307, and in Japanese Patent No. 4,005,237 as well as in German patent No. 3,724,341.

U.S. Pat. No. 5,120,538 is directed to a method of treating inflammation in apatient by administration of an effective dose of a pharmaceutical composition comprising essential oils extracted from tissues of Curcuma jiomestica, or Curcuma xahthorrhiza or both oils and curcuminoid substantially free of bis-desmethoxycurcumin.

U.S. Pat. No. 5,707,631 is directed to a therapeutic herbal composition including Trigonella foenum-graecum seed, Syzygium aromaticum fruit, Allilum sativum bulb, Cinnamomum zeylanicum bark, Saussurea costus root and Euphorbia lathyris bud together with sodium chloride (preferably sea salt).

U.S. Pat. No. 5,494,668 (Patwardhan) discloses a method of treating degenerative musculoskeletal diseases such as rheumatoid arthritis and osteoartliritis in an animal, typically a human, involving administering to jthe animal, typically enterally, in a convenient dosage form, a therapeutically effective amount of the beneficiated extracts of the plants Ashwagandha, Sallai Guggul, Turmeric, and Ginger, in a predetermined proportion relative to each other with or without other biologically active inorganic ingredients.

U.S. Pat. No. 5,683,698 (Chavali et al.) discloses an herbal formulation and its use for reducing/alleviating symptoms associated with rheumatoid arthritis, osteoarthritis, and reactive arthritis and for reducing the production of prό-inflammatory cytokines. The formulation contains an herbal extract from the Iroots, rhizomes and or vegetation of six herbal plant varieties, specifically, the spe'cies of Alpinia, ,Smilax, Tinospora, Tribulus, Withania, and Zingiber. The patent further discloses foods, beverages and medicaments in the form of capsules, tablets, liquids, and the like, containing the herbal formulation.

U.S. Pat. No. 5,916,565 (Rose et al.) discloses an orally administered composition for prophylaxis and therapy of joint and connective tissue disorders in vertebrates, wherein the composition contains metabolic precursors, herbal phytochemicals, and palatability agents. Suitable herbal phytochemicals are said to include cayenne, ginger, turmeric, yucca, Devil's claw, nettle leaf, Black Cohosh, alfalfa and celery seeds.

U.S. Pat. No. 5,888,514 (Weisman) discloses a composition for treating bone or joint inflammation in mammals, wherein the composition contains a systemically absorbable cartilage and an amninosaccharide and may optionally contain, among other ingredients, one or more extracts of an herb of the genus Withenia, of the bark of an herb of the genus Salix, or of a root of an herb of the genus Panax.

U.S. Pat. No. 5,908,628 (Hou) discloses compositions for treating osteoarthritis and rheumatoid arthritis, containing talc, silkworm excrement, and ingredients of plants of species of the genera Stephania, Coix, Pinellia, Prunus, Phellodendron, Sophora, Tetrapanax, Stemona, Glycyrrhiza, Tripterygium, Forsythia, and Siegesbeckia.

U.S. Pat. No. 5,788,971 (Togasaki) discloses an active oxygen free radical scavenging agent composed of green tea leaf extract containing epigallo catechin gallate and sunflower seed extract containing chlorogenic ac'id.

U.S. Pat. No. 5,854,291 (Laughlin, et al.) discloses a topically-applied pain reliever composition for treating such discomforts as arthritis pain, composed of capsaicin and, optionally, a plant extract selected from the group consisting of nettle extract, yarrow extract, coltsfoot extract, birch extract,] rosemary extract, horsetail extract, ginger extract, chamomile extract, comfrey extract, lavender extract, and bergamot extract.

U:S. Pat. No. 5,910,307 (Kwak, et al.) discloses a combined medicinal plant composition for alleviating acute/chronic inflammation, composed of Clematis Radix, Trichosanthes root, and Prunella Herba (which contains oleanolic acid ursolic acid) in a certain ratio.

Japanese Patent Publication No. 4,005,237 discl ses a combination of Cinnamomum sieboldii and Allium sativum for superoxide scavenging in the treatment of inflammatory disorders. German patent Publication No. 3,724,341 discloses a combination of Cinnamomum zeylanicum, Pumica granitum cortex, Cardamon zingiberaceie fruit and Piper longum fruit.

Although the use of various herbs have been described in related areas, the present invention provides a process of preparing the topical anti-inflammatory and analgesic preparation which comprises a different group 'of herbs with synergistic activity if used as per the present invention.

References:

1. Sharma JN and Jain JC. Indian J Pharmacol, 1978, 10:87.

2. Gujral ML et al. 'ind J Physiol Pharmacol! 1960, 4: 267-273.

3. Arora RB et al. Ind J Exp Biol 1971, 9: 403.

4. Arora RB et al. Ind J Med Res 1972, 60: 920.

5. Satyavati GV et al. Rheumatism 1969, 4:;141.-

6. Duwiejua M et al. Planta Medica 1993, 59: 12-16.

7. Sharma AK and Singh RH. Bull Med Ethhobot Res 1980, 1 : 262.

8. Mohiddin SG. Rheumatism 1974, 14: 97.1

9. Jain PK and Pande TK. J Res Ind Med Ybga Homeo 1976, 11:2.

10. Prasad GC and Udupa KN. J Res Ind Meμ 1972, 7(4): 29-34_:

11. Chopra SS et al. Ind J Med Res 1975, 63; 824-828.

12. Udupa KN and Prasad GC. Ind J Med Re^;s 1964, 52: 26.

13. Prasad GC and Udupa KN. Ind J Med Rejs 1963, 51 : 667-676.

14. Udupa KN and Prasad GC. Ind J Med Res 1964, 52: 480-487.

15. Kirtikar KR, Basu BD. Indian Medicinal (Plant Vol.IV p.2440-41.

16. The treatise on Indian Medicinal Plants.] Ed. Chatterjee A and Pakrashi SC. Vol.3. National Institute of Science Communication, New Delhi, 1997, p.76- 79.

17. Asmawi MZ et al. J Pharm Pharmacol 1SJ93, 45: 581-4.

Nadkarani KM. The Indian Materia Medica 3^rd Ed. Vol.l, Popular Prakashan, Bombay, 1976.

BJECTIVES OF THE PRESENT INVENTION:

It is an objective of the present invention to provide compositions based on the extraction process of herbal ingredients that! has potential analgesic and anti- inflammatory activity such as frozen, shoulder, stiff neck, backaches, and musculoskeletal pains and rheumatoid arthritis, dsteoarthritis, cervical and ankylosing spondylitis and sciatica.

It is another objective of the invention to produce pharmaceutical compositions from the cissus quadrangularis stem powder and costus speciosus stem powder.

A further objective of this invention is to provide synergistic compositions.

A further objective of this invention is to provide compositions aforesaid that act without exerting toxic or side effects.

DETAILED DESCRIPTION OF THE INVENTION:

The current invention in this application is the process for the preparation of compositions comprising of herbal ingredients. The synergistic compositions derived from a process of present invention are used to Relieve all painful and inflammatory conditions like rheumatoid arthritis, osteoarthritis, cervical and ankylosing spondylitis and sciatica, frozen shoulder, stiff neck, bach aches and musculoskeletal pains.

The process for the preparation of synergistic compositions essentially comprises of powders of cissus quadrangularis stem and costus speciosus stem. The process also comprises of powders of seedless fruit of terminalia chebula, terminalia bellarica, Embilica officinalis, melia azadirchta leaf, vitex negundo leaf, gum resin of commiphbora mukul. The process also optionally includes volatile oils like opium graveolens extract, pinus longifolia, campliora officinarum, cedrus deodara, Eucalyptus globules, and Melaleuca leucadendron.

The process of preparing the topical anti-inflammatory and analgesic preparation as per the present invention includes the following steps: a) Extraction of herbal ingredients water; b) Concentrating the extraction by boiling it; c) Filtration of the concentrated solution to remove residue; d) Addition of oil base to the filtrate; e) Removal of solvent by further boiling the mixture of base oil and filtrate; f) Resultant extract is allowed to cool; g) Addition of volatile oils ;to solution.

The following examples describe the invention however; they should not limit the scope of invention. Example I

Examples of types and amount of herbal ingredients in 60 ml used in preparation of topical anti-inflammatory / analgesic composition are described as below.

Ingredient Weight of ingredient In the composition

Extract of Cissus quadrangularis (Asthisamhara) 2.084 gm Extract of Costus speciosus (Bramhatirtha) 5.289 gm

II

Ingredient Weight of ingredient In the composition

Extract of Cissus quadrangularis (Asthisamhara)ι 0.521 gm Extract of Costus speciosus (Bramhatirtha) 4.171 gm in

Ingredient Weight of ingredient In the composition

Extract of Cissus quadrangularis (Asthisamhara)! 2.084 gm Extract of Costus speciosus (Bramhatirtha) 1.763 gm

IV

Ingredient Weight of ingredient In the composition

Extract of Cissus quadrangularis (Asthisamhara) 2.084 gm Extract of Costus speciosus (Bramhatirtha) 5.289 gm Gum resin of Commiphora mukul(Guggulu) 2.607 gm

V Ingredient Weight of ingredient In the composition

Extract of Cissus quadrangularis (Asthisamhara), 0.521 gm Extract of Costus speciosus (Bramhatirtha) 4.171 gm Gum resin of Commiphora mukul(Guggulu) 2.607 gm

VI

Ingredient Weight of ingredient In the composition

Extract of Cissus quadrangularis (Asthisamhara) 2.084 gm Extract of Costus speciosus (Bramhatirtha) 5.289 gm Gum resin of Commiphora mukul(Guggulu) 2.607 gm Extract of Vitex negundo(Nirgundi) 6.257 gm VII

Ingredient Weight of ingredient In the composition

Extract of Cissus quadrangularis (Asthisamhara), 0.521 gm Extract of Costus speciosus (Bramhatirtha) 4.171 gm Extract of Melia azadirchta(Nimba) 2.607 gm Extract of Vitex negundo(Nirgundi) 6.257 gm vπi

Ingredient Weight of ingredient In the composition

Extract of Cissus quadrangularis (Asthisamhara). 0.521 gm Extract of Costus speciosus (Bramhatirtha) 4.171 gm Extract of Melia azadirchta(Nimba) 2.607 gm Extract of Vitex negundo(Nirgundi) 6.257 gm Extract of Emblica offιcinalis(Amalaki) 1.0428 gm Gum resin of Commiphora mukul(Guggulu) 2.607 gm Extract of Terminalia Chebula(Haritaki) 1.0428 gm Extract of Terminali belle ica(Bibhitaka) 1.0428 gm

IX

Ingredient Weight of ingredient In the composition

Extract of Terminalia Chebula(Haritaki) 1.0428 gm Extract of Terminali bellerica(Bibhitaka) 1.0428 gm Extract of Emblica officinalis(Amalaki) 1.0428 gm Extract of Melia azadirchta(Nimba) 2.607 gm Extract of Vitex negundo(Nirgundi) 6.257 gm Extract of Cissus quadrangularis(Asthisamhara) 0.521 gm Extract of Commiphora mukul(Guggulu) 2.607 gm Extract of Costus speciosus(Bramhatirlha) 4.171 gm

X

Ingredient Percentage of ingredient

In the composition

Extract of Costus speciosus(Bramhatirtha) 11.83% Extract of Melia azadirchta(Nimba) 6.3% Extract of Terminali bellerica(Bibhitaka) 2.52% Extract of Emblica officinalis(Amalaki) 2.52% Extract of Commiphora mukul(Guggulu) 7.41% Extract of Vitex negundo(Nirgundi) 15.1% Extract of Cissus quadrangularis(Asthisamhara) 1.25% Extract of Terminalia Chebula(Haritaki) 2.52% Example π

Examples of types and amount of base oils used in preparation of topical anti- inflammatory / analgesic compositions are described as below.

Cotton seed oil Sesame oil Mustard oil

Cotton seed oil and Sesame oil in a ratio of 2:3 Cotton seed oil and Mustard oil in a ratio of 7:3 Sesame oil and Mustard oil in a ratio 'of 7:3 Cotton seed oil and Sesame oil in a ratio of 1 :4 Sesame oil and Mustard oil in a ratio !of 3.5:6.5 Cotton seed oil and Mustard oil in a ratio of 1 :3

Example πi

Examples of types and amount of volatile oils used in preparation of topical anti- inflammatory / analgesic composition are described as below.

Ingredient Weight of ingredient hi the composition

Pinus longifolia (Sarala) 2.600 gm Camphor (karpur) 3.259 gm Apium graveolens (Ajmoda) 2.600 gm Cedrus deodara (Devdaru oil) 1.629 gm Eucalyptus globulus (Nilgiri oil) 1.629 gm Melaleuca leucadendron 1.62*9 gm

II

Ingredient Weight of ingredient In the composition

Pinus longifolia(Sarala) 1.354 gm

Camphor(karpur) 3.259 gm

Apium graveolens(Ajmoda) 4.062 gm

Cedrus deodara(Devdaru oil) 0.529 gm

Eucalyptus globulus (Nilgiri oil) 1.629 gm

Melaleuca leucadendron 2.644 gm m

Ingredient Weight of ingredient In the composition

Pinus longifolia(Sarala) 4.062 gm

Camphor(karpur) 1.058 gm

Apium graveolens(Ajmoda) 2.354 gm

Cedrus deodara(Devdaru oil) 2.644 gm

Eucalyptus globulus (Nilgiri oil) 0.529 gm

Melaleuca leucadendron 1.529 gm IV

Ingredient Weight of ingredient

In the composition

Pinus longifolia(Sarala) 2.6θθ gm

Apium graveolens(Ajmoda) 2.60o gm

Cedrus deodara(Devdaru oil) 1.629 gm

Eucalyptus globulus (Nilgiri oil) 1.629 gm

V Ingredient Weight of ingredient

In the composition

Camphor(karpur) 3.25!9 gm

Apium graveolens(Ajmoda) 2.600 gm

Cedrus deodara(Devdaru oil) 1.629 gm

Eucalyptus globulus (Nilgiri oil) 1.629 gm

Melaleuca leucadendron 1.6|29 gm

VI

Ingredient Weight of ingredient

In the composition

Apium graveolens(Ajmoda) 2.600 gm

Cedrus deodara(Devdaru oil) 1.629 gm

Eucalyptus globulus (Nilgiri oil) _. I .62S9 gm

Example IV

Examples of types of processes describing Extraction, Concentrating the extract, Filtration, Addition of oils and cooling procedures used in preparation of topical anti- inflammatory / analgesic composition are described as below.

Process I :

Mix herbs Terminalia chebula, Tenninalia bellarica, Emblica officinalis, Melia azardichta, Vitex negundo, Cissus quadrangularis, commiphora mukul, and costus speciosus. Add solvent, which weighs 20 times jas much as the total weight of herbs into a mixture of herbs. Boil the mixture at 80 °C till the volume of solvent reduced to approximately half. After boiling filter the extract to get clear liquid. This filtrate was mixed with 3 times weight of base oil by weight of herbal ingredients and boil at 80 °C till all solvent gets removed and oil becomes completely free from solvent. The oily solution was allowed to cool. In a cool; oily solution add pinus longifolia, camphora officinarum, Apium graveolens, Cedrjus deodara, Eucalyptus globulus and Melaleuca leucadendron. Mix thoroughly to get bily liquid.

Process II :

Mix herbs Terminalia chebula, Terminalia bellarica, Emblica officinalis, Melia azardichta, Vitex negundo, Cissus quadrangularis, commiphora mukul and costus speciosus. Add solvent, which weighs 20 times las much as the total weight of herbs into a mixture of herbs. Add 3 times weight of base oil by weight of herbal ingredients. Boil the mixture at 80 °C till volume of solvent reduced to half. After boiling filter the extract to get clear liquid. This filtrate was further boiled at 80 °C till all solvent gets removed and oily solution becomes completely free from the solvent. The oily solution was allowed to cool. In a cool oily solution add pinus longifolia, camphora officinarum, Apium graveolens, Cedrus deodara, Eucalyptus globulus and Melaleuca leucadendron. Mix thoroughly to get bily liquid.

Process πi :

Mix herbs Terminalia chebula, Terminalia bellarica, Emblica officinalis, Melia azardichta, Vitex negundo, Cissus quadrangularis, and commiphora mukul. Add solvent, which weighs 20 times as much as the total weight of herbs into a mixture of herbs. Boil the mixture at 80 °C till volume of solvent reduced to half. After boiling filter the extract to get clear liquid. This filtrate was mixed with 3 times weight of base oil by weight of herbal ingredients and boil! at 80 °C till all solvent gets removed and oil becomes completely free from solvent. This is designated as Extract I. Take the herb costus speciosus and repeat the process as described for Extract I. The resultant oily solution is designated as Extract III

Mix the Extract I and Extract II and allow them to cool. In a cool oily solution add pinus longifolia, camphora officinarum, Apium graveolens, Cedrus deodara, Eucalyptus globulus and Melaleuca leucadendron. Mix thoroughly to get oily liquid.

Example V:

Examples of physicochemical characteristics of pharmaceutical compositions:

The herbal compositions derived from the process of present invention are also evaluated for its stability. The herbal compositions are evaluated at different test conditions of temperature and humidity (25° C /'60% RH for 36 months, and 40° C / 75% RH for 6 months). It was found that the herbal compositions are stable at room temperature as well as at accelerated condition for physicochemical characteristics and therapeutic efficacy.

NON-HUMAN ANIMAL TRIALS:

Pharmacologic research shows that the process for the preparation of compositions of the present invention has an anti-inflammatory effect on arthritis caused by Freund's adjuvant in rats. The compositions of the present invention also provide anti- inflammatory activity due to carrageenin-induced inflammation in rats.

Method of Evaluation:

I. Fraund's Adjuvant induced Arthritis in Rats:

Arthritis was induced in eight groups of 6 rats (Female Wistar, 180-200g, 8 week old), each by an intradermal injection of 0.05 ml of complete Freund's adjuvant (Sigma Laboratory, USA) in the right hind footpad. Six rats were not injected and served as nonadjuvant controls. All the seven preparations were locally applied once daily to the injected footpad for 7 'days. The inhibitory effect of test compositions was assessed by measurement of the paw volume by the volume displacement method (Plethysmometer, UGO BASILE, Italy) immediately before injection of complete Freund's adjuvant and at 4^th and 7^th day after the application. A group of six rats were not applied any preparation and served as positive control.

II. Carrageenin induced Acute Inflammation in Rats:

Acute inflammation was induced in eight groups of 4 rats (female Wistar rats, 180-200g, 8-9 weeks old), each by injecting 0.1 ml of carrageenin (1% w/v) solution in normal saline beneath the sub plantar region of the right hind paw- The paw volume of rats was measured with a plethysmometer (model 7140, UGO BASAILE, Italy) immediately before and at 2^nd, 3^rd and 4^th hour after carrageenin injection. All the seven compositions were locally applied half an hour after carrageenin application. The mean increases in paw volume were calculated and results are shown as percentage inhibition of] swelling compared with the control.

I. Fraund's Adjuvant induced Arthritis in Rats: The following examples

1-4 describe the evaluation of various herbal formulations in the treatment of arthritis caused by Fraund's adjuvant in rats.

Example 1:

Evaluation of the composition derived from the process of the present invention comprises of extract of Cissus Quadrangularis & Costus Speciosus in base oil. This composition now designated as composition 1, which has been evaluated in the treatment of arthritis caused by Freund's adjuvant in rats.

Single injection of 0.05 ml complete Freund's adjuvant produced a significant increase in paw volume as compared to nonadjuvant control at day 4 that is also maintained on day 7.

The protective effect, as calculated by percentage decrease in the paw volume, was found to be significant with composition 1 as compared to adjuvant control. Composition 1 has been found to decrease in paw volume by 40% and 36% on day 4 and day 7 respectively after single application in a day up to seven days. The results demonstrating the efficacy of herbal compositions 1 on the protection of arthritis have been shown in Table: 1.

Example 2:

Evaluation of the composition derived from the .process of the present invention comprises of extract of Cissus Quadrangularis, Costus Speciosus, Terminalia chebula, Terminalia bellarica, Emblica officinalis, Melia azardichta, Vitex negundo, and commiphora mukul in base oil along with volatile oils pinus longifolia, camphora officinarum, Apium graveolens, Cedrus deodara, Eucalyptus globulus and Melaleuca leucadendron. This composition now designated as composition 2, which has been evaluated in the treatment of arthritis caused by Freund's adjuvant in rats. Single injection of 0.05 ml complete Freund's adjuvant produced a significant increase in paw volume as compared to nonadjuvant control at day 4 that is also maintained on day 7.

The protective effect, as calculated by percentage decrease in the paw volume, was found to be significant with composition 2 ' as compared to adjuvant control. Composition 2 has been found to decrease in paw volume by 36% and 42% on day 4 and day 7 respectively after single application in a day up to seven days. The results demonstrating the efficacy of herbal composition 2 on the protection of arthritis have been shown in Table: 1.

Table : 1

Example 3:

Evaluation of the composition derived from the process . of the present invention comprises of extract of Cissus Quadrangularis or Costus Speciosus in base oil. This composition now designated as composition 3 !and composition 4, which has been evaluated in the treatment of arthritis caused by Freund's adjuvant in rats.

The compositions containing only Cissus Quadrangularis or Costus Speciosus (Composition 3 and 4) produced a 20% and 30% decrease in paw volume as compared to adjuvant control in rats with adjuvant-induced arthritis. This effect is less than the composition 1 which contains both ; Cissus Quadrangularis and Costus Speciosus. These results indicate that the costus and cissus when combined together give better effect. The results demonstrating the efficacy of herbal compositions 3 and 4 on the protection of arthritis have been shown in Table: 2.

Table : 2

Example 4

Removal of Cissus Quadrangularis and Gostus Speciosus both or Cissus Quadrangularis or Costus Speciosus from the process for preparing composition 2 has also been evaluated. These compositions are ; now designated as composition 5, composition 6 and composition 7 respectively^ which have been evaluated in the treatment of arthritis caused by Freund's adjuvant in rats.

The removal of cissus or costus, as in composition 6 and 7, from composition 2 described above leads to a drastic reduction in the activity, however, removals of both the ingredients provide a significant decrease inj a paw volume on day 7 as compared to adjuvant control. Composition 6 and 7 infact, does not produced any activity. However composition 5 decreased the paw volume by 26% on day 7 that is significantly different as compared to adjuvant φntrol. These results also confirm the essentiality of Costus and Cissus in the composition and also the synergistic action of both the ingredients. The results demonstrating the effect of herbal compositions 5, 6 and 7 on the protection of arthritis have been shown in Table: 3.

Table : 3

II. Carrageenin induced Acute Inflammation in Rats: The following examples 1-4 describe the evaluation of various herbal fonnulations in the treatment of acute inflammation caus'ed by carrageenin in rats.

Example: 1

Evaluation of the composition derived from the process of the present invention comprises of extracts of Cissus Quadrangularis |& Costus Speciosus in base oil. This composition now designated^' s composition 1, which has been evaluated in the treatment of acute inflammation caused by carrageenin in rats.

Single injection of 0.1 ml of Carrageenin produced a significant increase in paw volume as compared to control after 2^nd, 3^rd and ^th hours.

The protective effect, as calculated by percentage decrease in the paw volume, was found to be significant with composition 1 as compared to carrageenin control. Composition 1 has been found to decrease in paw volume by 50% at 2^nd and 3^rd hours and 36% at 4^!h hour respectively after single application. The results demonstrating the efficacy of herbal composition 1 on the protection of inflammation has been shown in Table: 4.

Example 2:

Evaluation of the composition derived from the process of the present invention comprises of extract of Cissus Quadrangularis, Costus Speciosus, Terminalia chebula, Terminalia bellarica, Emblica officinalis, Melia azardichta, Vitex negundo, and commiphora mukul ,in base oil along with volatile oils pinus longifolia, camphora officinarum, Apium graveolens, Cedrus deodara, Eucalyptus globulus and Melaleuca leucadendron. This composition .now designated as composition 2, which has been evaluated in the treatment of acute inflammation: caused by carrageenin in rats.

Single injection of 0.1 ml of Carrageenin produced a significant increase in paw volume as compared to control after 2^nd, 3^ld and 4^th hours.

The protective effect, as calculated by percentage decrease in the paw volume, was found to be significant with composition 2 as compared to carrageenin control. Composition 2 has been found to decrease in paw volume by 12%, 45% and 46% at 2^nd, 3^rd, and 4^th hour respectively after single application. The results demonstrating the efficacy of herbal composition on the protection of inflammation has been₍ shown in Table: 4.

Table: 4

Example 3:

Evaluation of the composition derived from the process of the present invention comprises of extract of Cissus Quadrangularis or Costus Speciosus in base oil. This composition now designated as composition 3 , and composition 4, which has been evaluated in the treatment of acute inflammation caused by carrageenin in rats.

The composition containing Cissus Quadrangularis (Composition 3) produced a decrease in swelling by 14% at 2^nd hour, 30% at3^rd hour and effect decreased to 13 % at 4^th hour. The composition containing Costus Speciosus (Composition 4) produced a decrease in swelling by 18% at 2^nd hour and 23-26% at 3^rd and 4^th hour. Thus, the composition containing only Cissus Quadrangularis or Costus Speciosus (Composition 3 and 4) produced a maximum of 30% decrease with composition 3 and a maximum of 26% decrease with composition 4 in paw volume as compared to carrageenin-induced acute inflammation. This effect is less than the composition 1 which contains both Cissus Quadrangularis and Costus Speciosus. So, the results indicate that the costus and cissus when combined together gives synergistic effect. The results demonstrating the efficacy of herbal compositions 3 and 4 on the protection of carrageenin-induced inflammation in rats have been shown in Table: 5.

Table: 5

Example 4

Removal of Cissus Quadrangularis and Costus Speciosus both or Cissus Quadrangularis or Costus Speciosus from the process for preparing composition 2 has also been evaluated. These compositions are ! now designated as composition 5, composition 6 and composition 7 respectively! which have been evaluated in the treatment of acute inflammation caused by carrageenin in rats.

The removal of cissus or costus, as in composition 6 and 7, from composition 2 described above leads to a drastic reduction in th'e activity, however, removals of both the ingredients provide a significant decrease inj a paw volume on 2^nd and 3^rd hour as compared to carrageenin control as in composition 5. Composition 6 and 7 infact, produced a maximum activity of 15% and 19% respectively. However, composition 5 decreased the paw volume by 44% on 2^nd hour and 37% at 3^rd hour that is significantly different as compared to carrageenin control. These results also confirm the essentiality of Costus and Cissus in the composition and also the synergistic action of both the ingredients. The results demonstratrrig the effect of herbal compositions 5, 6 and 7 oh the protection of arthritis have been shown in Table: 6.

Table: 6

HUMAN CLINICAL TRIALS:

A placebo controlled clinical trial was conducted on 88 patients with osteoarthritis with the composition derived from the present invention.

Patients were randomly divided in to two groups. The first group (the treatment group) consisted of 45 patients while there were 43 patients in second group (control group) In the treatment group, there were 22 males and 23 females. In control group, there were 18 males and 25 females. The patients within these two groups had no significant differences in the severity of illness.

Treatment:

Patients in the treatment group applied locally twice a day of the composition derived from the process of the present invention and patients in the control group applied placebo oil twice a day. The length of each treatment was 4 weeks. The clinical parameters were obtained before inclusion in thej study and after 4 weeks of treatment.

Observations: Following observations were made to find out efficacy:

^♦♦^♦ Pain at rest

❖ Pain on the use of joints

❖ Joint swelling ^♦♦^♦ Joint tenderness

❖ Range of movements

❖ 50 ft. walking time

❖ Duration of joint stiffness

❖ ARA functional class ^♦♦^♦ Visual analogue

Results:

All the parameters listed above were compared! with the placebo for all the patients before and after 4 week of receiving the treatment. Pain at rest was reduced to score 1.3 from 2.5 with greater relief with the treatment as compared to placebo. Pain on the use of joints also found greater relief with the treatment as compared to placebo. Joint swelling and joint tenderness reduced better iwith the treatment as compared to placebo., 50 ft. walking time was also reducedjby 10 minutes with the treatment as compared to 5 minutes with the placebo. The score for ARA functional class has been reduced to 1.2 from 2.4 with the treatment as compared to 1.8 from 2.5 in placebo group. Visual analogue score also improved 'significantly following treatment as compared to placebo. Thus the treatment of herbal composition gives better relief as compared to placebo group of patients. Toxicity and side effect observation:

All 88 patients showed no local adverse effebt during the treatment period and showed no skin reaction after the treatments.

Summary:

The study demonstrated that treatment group had significantly improved all clinical parameters except range of movement and duration of joint stiffness as compared to placebo. According to this study, the composition derived from the process of present invention provide efficacy for the treatment bf rheumatoid arthritis, spondylitis, osteoarthritis, and sciatica.

Claims

We claim:

1. The process of preparing the topical anti-inflammatory and analgesic preparation comprising of a) Extraction of herbal ingredients in an appropriate solvent; b) Concentrating the extraction of step a; c) Filtration of the concentrated solution of step b; d) Addition of oil base to the filtrate of step c; e) Removal of solvent of step d by appropriate means; f) Resultant extract is allo\ved to cool; g) Addition of volatile oils to^' solution of step f.

2. The process of preparing the topical anti-inflammatory and analgesic preparation wherein the herbal ingredients as claimed in claim 1 includes cissus quadrangularis stem powder and costus speciosus stem powder;

3. The process of preparing the topical anti-inflammatory and analgesic preparation wherein the herbal ingredients as claimed in claim 1 optionally includes any herb/s.

4. The process of preparing the topical anti-inflammatory and analgesic preparation wherein the herbal ingredients as claimed in claim 1 and 3 are selected from powders of seedless fruit of Terminalia chebula, Terminalia bellarica, Emblica officinalis, Melia azadirchta leaf, vitex negundo leaf, gum resin of commiphora mukul.

5. The process as claimed in claims 1-4 wherein the ratio, of each herbal ingredients to solvent is in a range of 0.5 ,: 1000 to 1 : 15.

6. The solvent claimed in claim 1 is preferably water.

7. A process of preparing the topical anti-inflammatory and analgesic preparation as claimed in claims 1, 5 and 6, whereiii temperature of extraction is around 60°C to around 100°C.

8. A process of preparing the topical anti-inflammatory and analgesic preparation as claimed in claims 1, and 1,' wherein temperature of extraction is preferably at about 70 -90°C.

9. A process of preparing the topical anti-inflammatory and analgesic preparation as claimed in claims 1, and 8, wherein temperature of extraction is more preferably about 80°C.

10. A process of preparing the topical anti-inflammatory and analgesic preparation as claimed in claim 1 and 7 wherein extraction step is continued till the solvent is concentrated between 1/4¹ to 3/4* of its original volume.

11. A process of preparing the topical anti-inflammatory and analgesic preparation as claimed in claim 1 and 10, wherein extraction step is continued till the solvent is concentrated preferably between 35% to 65% of its original volume.

12. A process of preparing the topical anti-inflammatory and analgesic preparation as claimed in claim 1 and 11 wherein extraction step is continued till the solvent is concentrated more preferably between 45% to 55% of its original volume, and filtered.

13. The oil bases as claimed in claim 1 are selected from cottonseed oil, sesame oil, mustard-oil or mixture thereof.

14. A process of preparing the topical anti-inflammatory and analgesic preparation as claimed in claim 1 and 13 wherein the|addition of oil base in about 0.5 to 10 times by weight of herbal ingredients to the filtrate.

15. A process of preparing the topical anti-inflammatory and analgesic preparation as claimed in claim 1 and 14; wherein the addition of oil base is preferably about 2 to 7 times by weight of herbal ingredients to the filtrate.

16. A process of preparing the topical anti-inflammatory and analgesic preparation as claimed in claim 1 and 15 wherein the addition of oil base is more preferably about 2.5 to 4.5 times by weight of herbal ingredients to the filtrate.

17. A process of preparing the topical anti-inflammatory and analgesic preparation as claimed in claims 1 and 16 wherein, mixture of filtrate and oil base is subjected to boiling at around 60°C to around 100°C till all solvent is removed.

18. A process of preparing the topical anti-inflammatory and analgesic preparation as claimed in claims 1 and 17 wherein] mixture of filtrate and oil base is subjected to boiling preferably at about 7Q-90°C till all solvent is removed.

19. A process of preparing the topical anti-inflammatory and analgesic preparation as claimed in claims 1 and 18 whereinj mixture of filtrate and oil base is subjected to boiling is more preferably at 80°C till all solvent is removed.

20. A process of preparing the topical anti-inflammatory and analgesic preparation as claimed in claims 1 and 19 wherein resultant extract is allowed to cool.

^'21. The volatile oils as claimed in claims 1 iare selected from extract of Apium graveolens, Pinus longifolia, Camphdra officinarum, Cedrus deodara, Eucalyptus globulus, Melaleuca leucadendron, Cinnamon oil, Clove oil, Pippermint oil, Piper nigrum oil, and Garlic oil.

22. The volatile oils as claimed in claims 1 and 21 are preferably extract of apium graveolens, Pinus longifolia, Camphora officinarum, Cedrus deodara, Eucalyptus globulus, Melaleuca leucadendron.

23. The volatile oils as claimed in claim 22ιare mixture of 5-15% by weight of pinus longifolia, 4-16% by weight of Camphora officinarum, 5-15% by weight of Apium graveolens extracts, 2-10% each by weight of cedus deodara, Eucalyptus globulus, Melaleuca leucadendron.

24. A process of preparing the topical anti-inflammatory and analgesic preparation as claimed in claims 1 and 21-23, wherein volatile oils are mixed with extract.

25. The process of preparing the topical anti-inflammatory and analgesic preparation as claimed in claims 1-4 wherein the ratio of each herbal ingredients to volatile oils is in a range of 0 to 20%. _t

26. The process of preparing the topical anti-inflammatory and analgesic preparation as claimed in claim 1-4 wherein herbal ingredients may be extracted individually or from a mixture thereof to get synergistic pharmaceutical compositions.

27. The synergistic pharmaceutical compositions as claimed in claim 26 are used to relieve all painful and inflammatory conditions.

28. The inflammatory conditions as claimedjin claim 27 are rheumatoid arthritis, osteoarthritis, cervical, and ankylosing spondylitis and sciatica.

29. The painful conditions claimed in claim 26 are conditions like frozen shoulder, stiff neck, backaches, and musculoskeletal pains and the like.

30. The synergistic pharmaceutical compositions claimed in claim 26 are applied topically.

31. The synergistic pharmaceutical compositions claimed in claims 26 and 30 are applied in form of oil, ointment; gel or spray.

32. The process of preparing the topical anti-inflammatory and analgesic preparation comprising the herbal ingredients claimed in claim 1-4 are in a concentration range of 0.5-5% by weight of cissus quadrangularis stem powder, 5-15% by weight of costus speciosus stem powder, 1-5% each of Terminalia chebula, Terminalia bellarica,! Emblica officinalis, leaf powder of 2-10% of Melia azadirchta, leaf powder ]of 10-20% of Vitex negundo, gum resin of 5.-15% of commiphora mukul in a finished formulation.

33. The process as claimed in claims 1-4 are substantially described herein in examples I-V.

34. The topical anti-inflammatory and analgesic preparations consisting of extract of costus speciosus and cissus quadrangularis in oil base along with volatile oil.

35. The topical anti-inflammatory and analgesic preparations as claimed in claim 34 optionally includes the extract of any herb/s.

36. The topical anti-inflammatory and analgesic preparations as claimed in claim 34 and 35 wherein the extract of herbs are selected from powders of seedless fruit of Terminalia chebula, Terminalia bellarica, Emblica officinalis, Melia azadirchta leaf, vitex negundo leaf, and gύm resin of commiphora mukul.

37. The topical anti-inflammatory and analgesic preparations as claimed in claim 34 wherein the oil base are selected from! cottonseed oil, sesame oil, mustard oil or mixture thereof.

38. The topical anti-inflammatory and analge'sic preparations as claimed in claim

34 wherein the volatile oils are selected from extract of Apium graveolens,

Pinus longifolia, Camphora officinarum, Cedrus deodara, Eucalyptus globulus, Melaleuca leucadendron, Cinnamon oil, Clove oil, Pippermint oil, Piper nigrum oil, and Garlic oil.

39. The topical anti-inflammatory and analg sic preparations as claimed in claim 34 and 38 wherein the volatile oils are preferably extract of apium graveolens, Pinus longifolia, Camphora officinarum, Cedrus deodara, Eucalyptus globulus, Melaleuca leucadendron.

40. The process of preparing the topical anti-inflammatory and analgesic preparations as claimed in 1-4 wherein the final product is green in colour.

41. The final product as claimed in claim 40 wherein the weight per ml is between 0.7 and 0.95.

42. The final product as claimed in claim 4Q wherein the saponification value is between 150 and 200. j

43. The final product as claimed in claim ! 40 wherein the_v refractive index is between 1.2 and 1.6.

44. The final product as claimed in claim 401 wherein the iodine value is between 75 and 100.

45. The final product as claimed in claim 40 wherein the acid value is not more than 20.