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WO2005077393A1 - Preparation a base d'herbes medicinales comportant des extraits d'adhatoda, d'hedychium et de curcuma comme sirop contre la toux - Google Patents

Preparation a base d'herbes medicinales comportant des extraits d'adhatoda, d'hedychium et de curcuma comme sirop contre la toux Download PDF

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WO2005077393A1
WO2005077393A1 PCT/IB2005/000136 IB2005000136W WO2005077393A1 WO 2005077393 A1 WO2005077393 A1 WO 2005077393A1 IB 2005000136 W IB2005000136 W IB 2005000136W WO 2005077393 A1 WO2005077393 A1 WO 2005077393A1
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organic solvent
extract
solution
extracting
pharmaceutical formulation
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PCT/IB2005/000136
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English (en)
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Rahul Singh
Aravind Padiyar
Anil Kanaujia
Navin Kumar Sharma
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Ranbaxy Laboratories Limited
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/906—Zingiberaceae (Ginger family)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/19—Acanthaceae (Acanthus family)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/906—Zingiberaceae (Ginger family)
    • A61K36/9066—Curcuma, e.g. common turmeric, East Indian arrowroot or mango ginger
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents

Definitions

  • the present invention relates to an herbal formulation comprising Adhatoda zeylanica, Hedychium spicatum and Curcuma longa. Also provided are processes for the isolation, detection, and quantification of the active phytochemicals found in the herbs.
  • Background of the Invention Coughing is an important protective reflex and plays a critical role in the physiological defense mechanism that protects the airways from noxious irritants and augments the muco-ciliary clearance of airway secretions. It is also a prime mechanism for clearing secretions from the lungs when the natural ciliary function is compromised by an acute or chronic infection.
  • a cough may be produced by inflammatory, mechanical, chemical and/or thermal stimulation of the cough receptors.
  • coughing is an important defense mechanism, in the form of an explosive expiration, for clearing secretions and inhaled extraneous substances from the tracheo- bronchial tree. It is associated with other protective processes such as broncho- constriction and mucus secretion.
  • Coughing in itself is not a disease but is often the most visible symptom in a wide variety of diseased states ranging from mild upper respiratory tract infection to serious illnesses.
  • coughing has two primary functions: (1) to prevent foreign material from entering the lower respiratory tract and (2) to clear foreign material and excessive secretions from the lower respiratory tract.
  • coughing inadequately serves its protective roles, atelectasis, gas-exchange abnormalities, pneumonia and bronchiectasis may ensue.
  • the Ayurvedic system of Indian traditional medicine provides many formulations concerning cough related disorders. A majority of the plants have already been investigated for their beneficial medicinal properties. In India, Ayurveda has carried out studies for many generations and recorded medicinal uses of plants for over 5000 years.
  • Vasaka Adhatoda zeylanica
  • Tulsi Ocimum tenuiflorum
  • Yashtimadhu Glycyrrhiza glabra
  • Kapoorkachri Hedychium spicatum
  • Sunthi Zingiber officinale
  • Pippali Piper longum
  • antakari Solanum xanthocarpum
  • Malayvacha Alphainia galanga
  • Haridra Haridra
  • Karpoor Cheinnamomum camphora
  • Guggulu Commiphora wightii
  • Draksha Vitis vinifera
  • Jufa Hyssopus officinalis
  • Guduchi Tinospora cordifolia
  • Jatiphal Myristica fragrans
  • Gojivha Onosma bracteatum
  • Amalaki Emblica of
  • Adhatoda zeylanica Syn: Adhatoda vasica This plant is found in the western and central regions of the sub-tropical Himalayas at an altitude of 1500-2000 m and is abundant in Punjab and Tamilanchal. It is a well- known plant drug of the Indian system of medicine and is used for the treatment of various diseases, particularly of the respiratory tract (Claeson et al., J. Ethnopharmacology 72; 1- 20, 2000). The plant is bitter, astringent, expectorant, febrifuge, styptic and tonic. Its leaves are especially used for irritable cough and in hemoptysis. The leaf-juice along with the roots is used in phthisis, cough, hemoptysis and asthma.
  • Ayurveda viz. Charak, Sushruta, Vagbhatta, Bhava Prakash, it is mentioned as a remedy for treating cold, cough, whooping cough, chronic bronchitis, asthma, epistaxis, tuberculosis, spasms and as an anthehriintic. It is an official drug of the Ayurvedic Pharmacopoeia of India. It is employed in different forms, such as fresh juice, decoction, infusion, powder, alcoholic extract, liquid extract and syrup. The leaves contain a very small amount of an essential oil.
  • the alkaloid content in the leaves is 0.2 - 0.4% and in the bark it is about 0.35% (The Wealth of India, Vol.l, 31- 32 (1948)).
  • the major quinazoline alkaloids are vasicine, vasicinine, vasicinol, vasicol, vasicoline, adhatodine, vasicolinone and anisotine. It has been shown that the alcoholic extract of A. vasica displays a marked dose dependent anti-tussive activity when given orally to guinea pigs in which the cough was induced by irritant aerosol. The activity was found to be comparable with codeine, suggesting it to be a potent anti-tussive agent (Dhuley et al., J.
  • vasicine Chemical modification of vasicine resulted in 6,7,8,9, 10,12-hexahydroazepino- ⁇ 2,l-b ⁇ -quinaxoline-12-one which exhibited significant bronchodilatory activity similar to sodium cromoglycate and aminophylline in rats under systemic anaphylaxis.
  • Semi- synthetic derivatives of vasicine including bromhexine and ambroxol are used as mucolytic agents because of their indirect effect on enliancement of lysozyme levels in bronchial secretions. Adhatoda has also been said to possess anti-inflammatory activity.
  • the alkaloidal fraction showed the most potent activity, which was found to be comparable to hydrocortisone.
  • the alcoholic extract of Adhatoda was found to be non-lethal in rats even when given in doses of 4 gm/kg.
  • the intra-peritoneal LD 50 of the extract was found to be 581 mg/kg.
  • Hedychium spicatum Ham ex Smith This plant is found throughout the year in the plains and sub-Himalayan tracts, ascending up to 1200 m.
  • the main active constituents of the Hedychium spicatum are Furanoid diterpene - Hedychenone, 7-hydroxy hedychenone which were isolated from rhizomes. Distilled from roots of Hedychium Spicatum it contains mainly p-methoxy cinnamic acid.
  • the dried rhizomes are subjected to steam-distillation to yield its principal constituent, the ethyl ester of p-methoxy cinnamic acid.
  • the essential oil contains ethyl cinnamate, d-sabinene, cineole, sesquiterpene, sesquiterpene alcohols, some pentadecane and traces of cirrnamaldehyde.
  • the rhizomes contain starch (52%o), organic acids including resinic acid, a glycoside, and ash (4.6%).
  • fifteen patients having tropical pulmonary eosinophilia were given dried powdered rhizomes of H. spicatum at a dose of 12 grams twice daily for four weeks. This resulted in a 60.54% reduction in total absolute eosinophil count, which was found to statistically significant.
  • the LD 5 o of the hexane soluble and benzene soluble fractions of the ethanolic extract was found to be more than 1 gm/kg with no signs of mortality (Srimal et al., Indian J Pharmacology 143-47, 1984).
  • Curcuma longa Linn This plant is a native of Southern Asia, but it is cultivated throughout all the States of India.
  • the major chemical constituents are curcuminoids ( ⁇ 6%), the yellow coloring principles of which curcumin constitutes 50-60%o; essential oil 2-7% with a high content of bisabolane derivatives.
  • Sesquiterpenes including curzerenone, curculone, curcumenol, pyrocurzerenone, turmerones are present in the rhizome in addition to desmethoxycurcumin, bidesmethoxycurcumin, dihydrocurcumin, phytosterols, fatty acids, phenolics and a noncyclic peptide turmerin, polysaccharides, viz., ukonan A, B, C and D composed of arabinose, xylose galactose, glucose rhamnose, mannose and galacturonic acid.
  • the active agent in Curcuma longa has been identified as curcumin.
  • curcumin was found to increase mucin release by directly acting on airway mucin secreting cells. This suggests a possible use as a mild expectorant (Lee et al., Planta Med 69; 523-26, 2003). Curcumin has been found to inhibit cyclooxygenase-2 and nitric oxide synthase enzymes that mediate the inflammatory process. It was also found to strongly suppress tumour promotion. Curcumin has shown beneficial anti-oxidant properties. Powder of Curcuma longa, when administered to patients with various respiratory diseases, was found to offer relief of symptoms like dyspnoea, cough and sputum.
  • cough syrups of both natural and synthetic origin available in the market. Acute cough and chronic cough are symptoms of conditions that may require medical attention. Generally, the cough syrups of synthetic origin produce good results but are always accompanied by one or the other side effects like drowsiness, sedation, dryness of mouth and respiratory tract and at times can be habit forming.
  • the drugs, which are used in the symptomatic treatment of the cough, are pharyngeal demulcents, expectorants, anti-tussives and bronchodilators.
  • An ideal cough formulation should: (1) liquify the thick mucous and at the same time should help in expectorating it out, (2) sooth the irritated respiratory mucosa, (3) stop the irritating dry cough, (4) protect the respiratory tract from allergens and (5) improve the immunity of the ⁇ respiratory tract.
  • Summary of the Invention hi one general aspect there is provided a herbal pharmaceutical formulation that includes extracts of Adhatoda, Hedychium and Curcuma, or a mixture of active ingredients that have been extracted from these herbs, and one or more pharmaceutically acceptable carriers and/or diluents.
  • Embodiments of the pharmaceutical formulation may include one or more of the following features.
  • the vasicine may make up from about 17.44 X 10-3 to about 15.06 X 10-3 % w/v
  • the ethyl p-methoxycinnamate may make up from about 10.20 X 10-3 to about 9.02 X 10-3 % w/v
  • the curcuminoids may make up from about 10.1 x 10-3 to about 8.47 x 10-3% w/v.
  • the Adhatoda extract may make up from about 1.0 % w/v to about 5.0 % w/v
  • the Hydechium extract may make up from about 0.1 % w/v to about 0.6 % w/v
  • the Curcuma extract may make up from about 0.1 % w/v to about 0.7 % w/v.
  • the pharmaceutical formulation may be intended for oral use as a cough syrup.
  • the pharmaceutical formulation may be prepared by: a. mixing a therapeutically effective amount of Adhatoda, Hedychium and Curcuma to get a combined extract; b. adding one or more pharmaceutically acceptable carriers and/or diluents to the combined extract to form a final mixture; and c.
  • Embodiments of the process of making the pharmaceutical formulation may further include detecting and quantifying the curcumin in the pharmaceutical formulation.
  • the detecting and quantifying may include: a. preparing a reference standard stock solution in an organic solvent; b. preparing standard curves by using the solution of step a) and a blank organic solvent; c. measuring the absorptions of the standard stock solution and a blank organic solvent at particular wavelengths after step b); and d. calculating the percentage curcuminoids in the formulation after step c).
  • the wavelength for measuring absorption may be ⁇ max 418 nm.
  • the preparation of the pharmaceutical formulation may still further include detecting and quantifying vasicine and ethyl p-methoxycinnamate in the pharmaceutical formulation.
  • the detecting and quantifying may include: a. extracting the formulation with one or more organic solvents or mixtures thereof optionally containing water or base; b. concentrating the extracts of step a) and reconstituting the residue in second organic solvent; c. spotting the solution obtained in step b) against a standard phytochemical marker on a HPTLC plate; d. developing the HPTLC plate of step c) in a mobile phase; e. optionally spraying or applying the detection reagent on the HPTLC plate of step d); f. scanning the plate of step e) at particular wavelengths; and g. detecting and quantifying vasicine and ethyl p-methoxycinnamate after step f).
  • a process for the isolation of the phytochemical marker compound vasicine from Adhatoda zeylanica include: a. extracting a selected powdered part of the plant with an organic solvent and then concentrating the extract to form a concentrate; b. acidifying the concentrate and extracting the concentrate with a second organic solvent; c. basifying the concentrate and extracting the concentrate with the second organic solvent; d. concentrating the organic extracts; and e. isolating vasicine.
  • the isolation may be by crystalhzation.
  • the organic solvent may be water soluble lower alkanols.
  • the water soluble alkanols may be one or more of methanol, ethanol, n-propanol, isopropanol and mixtures thereof.
  • the acidification of the concentrate may be performed with an aqueous organic or inorganic acid.
  • the acidification may be performed with one or more of sulphuric acid, hydrochloric acid, acetic acid, formic acid, phosphoric acid, nitric acid and mixtures thereof.
  • the second organic solvent may be one or more of non-polar aliphatic, cycloalkyl solvents, ethers, esters, chlorinated hydrocarbons, ketones and mixtures thereof.
  • the basification of the concentrate may be performed with one or more of ammonia, ammonium hydroxide, triethylamine, dimethylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, calcium carbonate, calcium hydroxide and mixtures thereof.
  • the process further include identifying vasicine in the extract. The identifying includes: a. after extracting the selected powdered part of the plant with an organic solvent, optionally filtering to form a test solution; b. applying a reference standard and test solution to a chromatoplate; c. developing the chromatoplate in a mobile phase; e. drying the chromatoplate and spraying it with a spraying/developing agent; and f.
  • the process may still further include estimating the total alkaloid content in the Adhatoda extract by: a. after extracting the selected powdered part of the plant with an organic solvent, acidifying the extract with an acid solution, refluxing, and filtering to form a filtrate; b. extracting the filtrate with an organic solvent to remove the organic compounds from the aqueous extract; c. basifying the aqueous extract with a base; d. extracting the solution with the organic solvent; e. concentrating/evaporating the solution to form a residue; f. drying the residue; and g. estimating the total alkaloid content.
  • a process for the isolation of the phytochemical marker compounds ethyl p-methoxycinnamate and curcumin from the plants Hedychium spicatum and Curcuma longa includes: a. extracting the selected powdered part of the plant with an organic solvent optionally containing water; b. concentrating the extracts; c. extracting the concentrated extracts with a second organic solvent and, optionally, filtering the solution to remove the non-polar impurities; d. purifying the resultant organic extracts by column chromatography; and e. detecting/isolating the phytochemical markers.
  • Embodiments of the process of isolating may include one or more of the following features.
  • the isolation of the phytochemical markers may be by crystallization.
  • the organic solvent may be water soluble lower alkanols.
  • the second organic solvent may be one or more of non-polar aliphatic, cycloalkyl solvents, ethers, esters, chlorinated hydrocarbons, ketones and mixtures thereof.
  • the process may further include identifying the ethyl p-methoxycinnamate or curcumin in the extract. The identifying includes: a. after extracting the selected powdered part of the plant with an organic solvent, optionally filtering to form a test solution; b. applying a reference standard and the test solution to a chromatoplate; c. developing the chromatoplate in a mobile phase; d.
  • the process may further include estimating the curcuminoid content in the Curcuma extract.
  • the estimating includes: a. after extracting the selected powdered part of the plant with an organic solvent, mixing the extract with an organic solvent; b. filtering the solution of step a); c. measuring the absorbance of the solution of step b) against an organic solvent as a blank and then calculating the curcuminoids content.
  • the process of estimating may include one or more of the following features.
  • the organic solvent may be one or more of non-polar aliphatic, cycloalkyl solvents, ethers, esters, chlorinated hydrocarbons, ketones, lower alkanols and mixtures thereof.
  • the absorbance may be measured at a wave length of 418 nm.
  • Ill shows TLC photograph of standard Curcumin against seven different experimental batches of cough syrup.
  • Fig. IV shows HPTLC chromatogram of Vasicine extracted from the syrup against standard Vasicine.
  • Fig. V shows HPTLC chromatogram of ethyl p-methoxycinnamate extracted from the syrup against Standard ethyl p-methoxycinnamate.
  • the present inventors have a reasoned belief that three indigenous herbs, Adhatoda, Curcuma and Hydechium, are time-proven for their role in cough and related disorders and are known to enhance the immunity as well, h combination, they will provide a better management of cough.
  • A. vasica is said to promote good voice and is especially used as 'Kapha-nihsaaraka (expectorant) and as a 'Kaphaghn ⁇ ' (mucolytic) agent. It also has a specific property of 'Chedana' (scraps and liquefies the thick viscid cough) along with being a good 'Kapha- nihsaaraka' (expectorant) drug.
  • C. longa is 'Deepana' i.e.
  • H. spicatum is 'Kaphaghna' (mucolytic), 'Vedanaasthapana' (analgesic) and 'Jwaraghna' (anti-pyretic).
  • the formulation can be used in at least the following conditions: (1) allergic cough, (2) dry irritating cough, (3) productive cough and (4) smoker's cough
  • the cough syrup of the present invention contains select herbs, along with throat soothers, which provide quick relief from coughs and prevent reoccurrence. Also the formulation is alcohol free, resulting in no drowsiness. Ayurvedic medicines or herbal formulations are often criticized by the Western world and by regulatory agencies for the fact that there is no standardization or quantification of active principles in the dosage form.
  • the present inventors have also provided a method of standardizing the formulation by adopting certain strict criterion for selecting raw materials, processing of the extraction of the herbs and manufacturing of the formulation.
  • the present inventions provide a method of quantification of the active phytochemicals present in the formulation.
  • the present invention relates to a new herbal formulation which has been found to be effective in treatment and management of cough.
  • the formulation of present invention ensures not only symptomatic relief from cough but also to enhance the host-defense mechanism in order to strengthen the immune system and at the same time is devoid of toxic side effects.
  • Also provided is a process for the preparation and quantitative analysis of the individual phytochemicals used in the herbal formulation.
  • the combination of herbs has been selected on the basis of classical Ayurvedic literature survey and research studies conducted till date to work synergistically against coughs of varied etiologies.
  • the herbal pharmaceutical formulation includes extracts of Adhatoda, Hedychium and Curcuma or a mixture of their respective active ingredients that have been extracted along with one or more pharmaceutically acceptable excipients. It has now been found that the active ingredients of the herbs can be isolated and quantified.
  • the process for the isolation of the phytochemical marker compound-Vasicine as denoted by Formula I,
  • FORMULA I from Adhatoda zeylanica includes: a) extracting the selected powdered part of the plant with a suitable organic solvent, optionally containing water, and then concentrating the extract; b) acidifying the concentrate of step a) and extracting it with second organic solvent; c) basifying the concentrate obtained in step b) and extracting it with second organic solvent; d) concentrating the organic extracts obtained in step b) and c); and e) isolating the phytochemical marker, which may optionally be completed by crystallization.
  • Vasicine is present in leaves of Adhatoda zeylanica.
  • Adhatoda zeylanica should be crushed and powdered so that the particle size of the powder is such that not less than (NLT) 95 % of the particles pass through a size #30 mesh screen.
  • This powder is extracted three times with an organic solvent. Suitable organic solvents include one or more of water soluble lower alkanols, such as methanol, ethanol, n-propanol and isopropanol and mixtures thereof at a temperature between 35°C to 80°C.
  • the powder is extracted at the reflux temperature of the solvent used.
  • the combined extract is then concentrated under reduced pressure.
  • the concentrated extract is then suspended in an acid solution, which may be optionally aqueous in nature.
  • Suitable acid solutions may be organic or inorganic and include one or more of sulphuric acid, hydrochloric acid, acetic acid, formic acid, phosphoric acid, nitric acid and mixtures thereof. The solution is then repeatedly partitioned with a second organic solvent.
  • Suitable second organic solvents include one or more of non-polar aliphatic or cycloalkyl solvents, such as hexane, heptane, petroleum ether, cyclohexane; ethers such as diethyl ether, diisopropyl ether; esters, such as ethyl acetate, methyl acetate, ethyl formate, methyl formate, isobutyl acetate, n-butyl acetate; chlorinated hydrocarbons, such as methylene chloride, ethylene chloride, chloroform and carbon tetrachloride; ketones, such as acetone, ethyl methyl ketone, diisobutyl ketone, methyl isobutyl ketone; and mixtures thereof.
  • non-polar aliphatic or cycloalkyl solvents such as hexane, heptane, petroleum ether, cyclohexane
  • ethers
  • the organic phase is separately collected and the aqueous phase is basified with the base.
  • Suitable bases include one or more of ammonia, ammonium hydroxide, triethylamine, dimethylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, calcium carbonate, calcium hydroxide and mixtures thereof.
  • the basified aqueous phase is repeatedly partitioned with the second organic solvents described above and the collected organic phases are combined.
  • the combined organic layer obtained is then freed from traces of water by passing it through an anhydrous sodium sulphate.
  • the organic solvent is recovered under reduced pressure to get a solid light brown residue, which is crystallized from the organic solvent discussed above.
  • Formula III from the plants Hedychium spicatum and Curcuma longa respectively includes: a) extracting the selected powdered part of the plant with a suitable organic solvent, which may optionally contain water; b) concentrating the extracts obtained in step a); c) extracting the concentrated extracts of step b) with a second organic solvent, and if required, filtering the solution to remove the non-polar impurities; d) purifying the resultant organic extracts of step c) by column chromatography; and e) detecting and isolating the phytochemicals markers, optionally by crystallization, after step d). Ethyl p-methoxycinnamate is present in the rhizomes of Hedychium spicatum.
  • the rhizomes of Hedychium spicatum should be powdered to a particle size wherein not less than 95% material should pass through size #30 mesh. This is extracted three times with an organic solvent.
  • Suitable organic solvents include one or more of water soluble lower alkanols, optionally containing water, such as methanol, ethanol, n-propanol and isopropanol or mixtures thereof at a temperature between 35 to 80°C.
  • the powder is extracted at the reflux temperature of the solvent used.
  • the combined extracts are then concentrated under reduced pressure.
  • the concentrated extracts are then mixed with water and the aqueous layer is washed with second organic solvents.
  • Suitable second organic solvents include one or more of non- polar aliphatic or cycloalkyl solvents, such as hexane, heptane, petroleum ether, cyclohexane; ethers, such as diethyl ether, dusopropyl ether; esters, such as ethyl acetate, methyl acetate, ethyl formate, methyl formate, isobutyl acetate, n-butyl acetate; chlorinated hydrocarbons, such as methylene chloride, ethylene chloride, chloroform and carbon tetrachloride; ketones, such as acetone, ethyl methyl ketone, diisobutyl ketone, methyl isobutyl ketone; and mixtures thereof.
  • non- polar aliphatic or cycloalkyl solvents such as hexane, heptane, petroleum ether, cyclohexane
  • the organic washings are pooled together, dried over a suitable drying agent and filtered.
  • the organic extracts are further concentrated under reduced pressure and subjected to column chromatographic purification through a silica gel column and eluted with the second organic solvents in the increasing order of polarity.
  • the fractions are collected separately.
  • the fractions are scanned for ethyl p-methoxycinnamate presence by Thin Layer Chromatography (hereinafter referred to as TLC) using chloroform: methanol :: 9:1 mobile phase and Anisaldehyde in sulphuric acid as a developing spray.
  • TLC Thin Layer Chromatography
  • the crude ethyl p-methoxycinnamate is then crystallized from the second organic solvent.
  • the identity of this phytochemical was further confirmed through spectroscopic data generated.
  • Curcumin is found in the rhizomes of Curcuma longa.
  • the rhizomes are powdered so the particle size of the powder is such that not less than 95 % material should pass through a size #30 mesh.
  • This powder is extracted in the similar manner as described in the case of ethyl p-methoxycinnamate.
  • the concentrated extract is then subjected to column chromatographic purification through silica gel 100-200 mesh column and eluted with second organic solvents in the increasing order of polarity. The fractions are collected separately.
  • the fractions are scanned for the presence of curcumin by TLC using chloroform:methanol::95:5 mobile phase and detection is done under a UN / Fluorescence detector.
  • the fractions having curcumin as observed by TLC pattern are combined and concentrated under vacuum.
  • the crude curcumin is then crystallized from the solvent selected as the second organic solvent.
  • a method of identification of the active phytochemicals vasicine, ethyl p-methoxycinnamate and curcumin from their respective plant extracts includes: a. applying the reference standard and test solution to the chromatoplate; b. developing the chromatoplate of step (a) in a suitable mobile phase; c.
  • step (c) identifying vasicine, ethyl p-methoxycinnamate or curcumin after step (c).
  • the reference standard solution is prepared by dissolving vasicine, ethyl p- methoxycmnamate or curcumin separately in an organic solvent and optionally filtering the solution.
  • the test solution is prepared by dissolving the extract of Adhatoda, Hedychium or curcuma separately in an organic solvent and optionally filtering the solution.
  • Suitable organic solvents include one or more of lower alkanols, such as methanol, ethanol, n-propanol, isopropanol and mixtures thereof.
  • Suitable solvents used for the mobile phase include one or more of methanol, ethanol, n-propanol, isopropanol, hexane, heptane, petroleum ether, cyclohexane, diethyl ether, dusopropyl ether, ethyl acetate, methyl acetate, ethyl formate, methyl formate, isobutyl acetate, n-butyl acetate, methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, acetone, ethyl methyl ketone, diisobutyl ketone, methyl isobutyl ketone, 1,4- dioxane, toluene, ammonia solution, glacial ace
  • Suitable spraying/developing reagents include one or more of anisaldehyde- sulphuric acid reagent, glacial acetic acid, sulphuric acid, dragendorff s reagent and mixtures thereof.
  • the method of identification of vasicine, ethyl p-methoxycinnamate and curcumin in their respective plant extracts is performed through thin layer chromatography using a silica gel 60 F 254 pre-coated Aluminium foil plate with layer thickness 0.2 mm (1.05554, Merck).
  • Dragendorff s and Anisaldehyde in sulphuric acid are used as spraying or detecting reagent for Vasicine and ethyl p-methoxycinnamate respectively.
  • the photograph of the developed TLC after scanning is taken using Camag's photodocumentation unit in visible/fluorescent light.
  • a method for the estimation of total alkaloids content in Adhatoda extracts includes: a. acidifying the plant extract with an acid solution, optionally containing water, refluxing and filtering it; b. extracting repeatedly the filtrate of step a) with an organic solvent to remove the organic components from the aqueous extract; c. basifying the combined aqueous extract of step b) with a base; d. extracting the solution of step c) with an organic solvent; and e. concentrating/evaporating and then drying the product of step d) for estimating the total alkaloid content.
  • the acid solution used may optionally be aqueous in nature.
  • Suitable acid solutions may be organic or inorganic including one or more or sulphuric acid, hydrochloric acid, acetic acid, formic acid, phosphoric acid, nitric acid and mixtures thereof.
  • Suitable organic solvents include one or more of non-polar aliphatic and cycloalkyl solvents, such as hexane, heptane, petroleum ether, cyclohexane; ethers, such as diethyl ether, dusopropyl ether; esters, such as ethyl acetate, methyl acetate, ethyl formate, methyl formate, isobutyl acetate, n-butyl acetate; chlorinated hydrocarbons, such as methylene chloride, ethylene chloride, chloroform and carbon tetrachloride; ketones, such as acetone, ethyl methyl ketone, diisobutyl ketone, methyl isobutyl ketone; and mixtures thereof.
  • non-polar aliphatic and cycloalkyl solvents such as hexane, heptane, petroleum ether, cyclohexane
  • ethers
  • Suitable bases include one or more of ammonia, ammonium hydroxide, sodium hydroxide, calcium hydroxide, calcium carbonate, potassium hydroxide, potassium carbonate and mixtures thereof.
  • the Adhatoda extract may be mixed with hydrochloric acid and refluxed on a water bath for a half an hour and then diluted with water. The resulting mass is then filtered through a Whatman No. 41 filter paper. The clear filtrate is extracted with chloroform for a minimum of four times and the chloroform extract is discarded. The aqueous layer is then basified with a dilute ammonia solution (up to pH 9-10) and extracted with chloroform.
  • the chloroform extracts are then dried and evaporated in a pre-weighed beaker to dryness on a water bath.
  • the extracts are dried in an oven for 1 hour at a temperature of 105°C and then cooled in a descicator and weighed.
  • LOD equals the loss on drying. Also provided is a method for the estimation of the curcuminoid content in a Curcuma extract. The method includes: a. mixing the extract with an organic solvent; b. filtering the solution of step a); and c. measuring the absorbance of the solution of step b) against the organic solvent as a blank and then calculating the curcuminoid content.
  • Suitable organic solvents includes one or more of non-polar aliphatic or cycloalkyl solvents, such as hexane, heptane, petroleum ether, cyclohexane; ethers, such as diethyl ether, diisopropyl ether; esters, such as ethyl acetate, methyl acetate, ethyl formate, methyl formate, isobutyl acetate, n-butyl acetate; chlorinated hydrocarbons, such as methylene chloride, ethylene chloride, chloroform and carbon tetrachloride; ketones, such as acetone, ethyl methyl ketone, diisobutyl ketone, methyl isobutyl ketone; lower alkanols, such as methanol, ethanol, n-propanol, isopropanol and mixtures thereof.
  • non-polar aliphatic or cycloalkyl solvents
  • the organic solvent used as a blank for measuring the absorbance in step c) represents the organic solvent alone (e.g. without plant extract).
  • methanol is added to the curcuma extract and the solution is sonicated in an ultrasonic water bath. The soluted is filtered through a Whatman No. 41 filter paper and the absorbance of the solution is measured at 425 nm using methanol as blank.
  • ASPL equals the absorbance of sample at 425 nm.
  • a process for the preparation of a herbal pharmaceutical formulation which comprises extracts of Adhatoda, Hedychium and Curcuma or a mixture of active ingredients that have been extracted from these herbs with pharmaceutically acceptable carriers and/or diluents.
  • the process includes: a. mixing the individual extract of Adhatoda, Hedychium and Curcuma in a therapeutically effective amount to get a combined extract; b. adding one or more pharmaceutically acceptable carriers and/or excipients; and c. clarifying the final mixture by a suitable means if required.
  • the extracts may be mixed at a concentration range of: Adhatoda extract containing vasicine in a quantity of about 10 mg/100 ml to about 5000 mg / 100 ml; Hedychium extract containing ethyl p-methoxycinnamate in a quantity of about 10 mg/100 ml to about 5000 mg/100 ml; and Curcuma extract containing curcumin in a quantity of about 10 mg/100 ml to about 5000 mg/100 ml.
  • the extracts are mixed together and one or more pharmaceutically acceptable carriers are added.
  • Suitable pharmaceutically acceptable carriers include one or more of water miscible pharmaceutically acceptable co-solvents comprising propylene glycol, sorbitol, glycerol, polyethylene glycol and mixtures thereof. Purified water may also be added to the extract. The resultant mixture is then optionally filtered through a Sparkler Filter/centrifuge to remove any insoluble foreign particulate matter. To the clear solution obtained pharmaceutically acceptable preservatives may be added. Suitable pharmaceutically acceptable preservatives include one or more of propyl paraben, methyl paraben, and quaternary ammonium salts, such as cetrimide and mixtures thereof along. Optionally, one or more suitable flavoring agents and sequestering agents may be added.
  • the formulation can be made palatable by adding to it one or more sweetening agents.
  • suitable sweetening agents include one or more of invert sugar syrup, xylitol, mannitol, sugar syrup, jaggery, honey and maltose syrup. Non-sugar based sweetening agents may also be used.
  • the syrup obtained is then finally filtered through a size #100 mesh nylon cloth to remove the foreign particulate matter.
  • the oral syrup can be then packed in a suitable container and stored in a cool, dry place away from direct sunlight.
  • the invention also provides a method for the detection and quantification of vasicine and ethyl p-methoxycinnamate in a herbal pharmaceutical formulation, which comprises extracts of Adhatoda, Hedychium and Curcuma or a mixture of active ingredients that have been extracted from these herbs with pharmaceutically acceptable carriers and/or diluents.
  • the method includes: a. extracting the formulation with an organic solvent, optionally containing water or base; b. concentrating the extracts of step a) and reconstituting the residue in a second organic solvent; c. spotting the solution obtained in step b) against a standard phytochemical marker on a HPTLC plate; d.
  • step f) developing the HPTLC plate of step c) in a mobile phase; e. optionally spraying or applying the detection reagent on the HPTLC plate of step d); f. scanning the plate of step e) at particular wavelengths; and g. detecting and quantifying Vasicine and ethyl p-methoxycinnamate, after step f).
  • the oral syrup prepared above is further diluted with distilled water and extracted with an organic solvent. The extracts in organic solvent are dried over a suitable drying agent and then concentrated under a vacuum to remove the organic solvent. The residue obtained is reconstituted in an aliquote of the second organic solvent.
  • test solution is spotted against standard phytochemical marker solutions on HPTLC plates and the plates are allowed to develop in a saturated chamber containing a mobile phase. After complete development, the plates are optionally sprayed with a solution of spray reagents and dried in oven at 105°C for about 5 minutes. The plates are then scanned at various wavelengths to detect and quantify the phytochemical markers present in the formulation against standard phytochemical markers.
  • Suitable organic solvents include one or more of alkanols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol and n-octanol; ketones selected from acetone, ethyl methyl ketone, methyl isobutyl ketone and diisobutyl ketone; esters selected from methyl formate, ethyl formate, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate and tert-butyl acetate; chlorinated hydrocarbons selected from methylene chloride, chloroform, carbon tetrachloride and ethylene chloride; aromatic hydrocarbons selected from xylene, toluene, benzene, substituted benzen
  • a suitable second organic solvent includes one or more of methanol, ethanol, isopropanol, n-propanol, acetone, acetonitrile, diethyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, tetrahydrofuran and mixtures thereof.
  • the standard phytochemical marker solutions are prepared by dissolving a known quantity of each of vasicine and ethyl p-methoxycinnamate separately in a known quantity of the second organic solvent mentioned above. The solution may be sonicated and then made up to a desired fixed volume using the same solvent. These standard solutions are used as reference standard solutions.
  • Suitable spraying reagents include one or both of Dragendorff s reagent and anisaldehyde sulphuric acid reagent.
  • the spraying reagent may be Dragendorff s reagent for the detection of Vasicine and Anisaldehyde sulphuric acid reagent for the detection of ethyl p-methoxycinnamate.
  • HPTLC was performed using a silica gel 60 F 25 pre-coated Aluminium foil plate with a layer thickness of 0.2 mm (1.05554, Merck). The reference and test solutions are applied on the plates in a fixed volume using a hypodermic syringe. The distance between two spots is kept at about 10 mm having a band length of about 8 mm.
  • the mobile phase used can be selected from a mixture of solvents described as first organic solvent.
  • the mobile phase maybe 1,4- dioxane: toluene:methanol: ammonia present at a ratio of 50:2:2:1 for the detection of vasicine or chloroform: acetone present at a ratio of 80 : 20 for the detection of ethyl p-methoxycinnamate.
  • the mobile phase is placed in a glass chamber having dimensions of 20 cm x 10 cm. After saturating the glass chamber with the mobile phase for about 60 minutes, HPTLC plates are placed into the chamber and the development distance of 8 cm from point of application is selected.
  • the plate was removed from the chamber and dried using hot air blower.
  • the plate is scanned at two wavelengths; 292 nm for the determination of vasicine and 310 nm for determination of ethyl p-methoxycinnamate using Camag's High Performance Thin Layer Chromatographic system equipped with Linomat V and Photo documentation unit.
  • the content of ethyl p-methoxycinnamate is calculated by using Formula II provided below: % Content of Ethyl p-methoxycinnamate x 100
  • a SPL Area of sample corresponding to vasicine or ethyl p-methoxycinnamate
  • a S T D Area of Standard solution of vasicine or ethyl p-methoxycinnamate
  • D STD Dilution of reference standard solution
  • D SPL Dilution of test sample
  • the TLC plate after spraying with spray reagent and drying, can be photographed using the Camag's photodocumentation unit.
  • the TLC is shown here as Figure I and Figure II in the accompanied drawing.
  • the HPTLC cliromato grams of two different phytochemical markers are shown as
  • Figure IV (Vasicine) and Figure V (Ethyl p-methoxycinnamate). Also provided is a method for the detection and quantification of curcumin in a herbal pharmaceutical formulation, which comprises extracts of Adhatoda, Hedychium and Curcuma or a mixture of active ingredients that have been extracted from these herbs with pharmaceutically acceptable carriers and/or diluents.
  • the method includes: a. preparing a reference standard stock solution in a organic solvent; b. preparing standard curves by using the solution of step a) and a blank organic solvent; c. measuring the absorptions of standard stock solution and a blank organic solvent at particular wavelengths after step b); and d.
  • the reference standard stock solution is prepared by dissolving curcuminoids in an organic solvent.
  • Suitable organic solvents include one or more of non-polar aliphatic or cycloalkyl solvents, such as hexane, heptane, petroleum ether, cyclohexane; ethers, such as diethyl ether, diisopropyl ether; esters, such as ethyl acetate, methyl acetate, ethyl formate, methyl formate, isobutyl acetate, n-butyl acetate; chlorinated hydrocarbons, such as methylene chloride, ethylene chloride, chloroform and carbon tetrachloride; ketones, such as acetone, ethyl methyl ketone, diisobutyl ketone, methyl isobutyl ketone; lower alkanols, such as methanol, ethanol
  • a method of treating cough of varied etiologies in a patient in need thereof includes administering a pharmaceutical composition which comprises extracts of Adhatoda zeylanica, Hedychium spicatum and Curcuma longa and one or more pharmaceutically acceptable carriers/excipients.
  • a pharmaceutical composition which comprises extracts of Adhatoda zeylanica, Hedychium spicatum and Curcuma longa and one or more pharmaceutically acceptable carriers/excipients.
  • the following examples are intended to illustrate the invention and not to be construed as limiting the scope of the invention in any way.
  • EXAMPLE 1 Isolation of Vasicine from Adhatoda Zeylanica Leaves Powdered leaves of A. zeylanica (1.0 Kg) were extracted three times with methanol (3 x 3.5 Ltrs) at 65° C for 4 hours each.
  • the combined methanolic extract was concentrated to 1/5 of its original volume under reduced pressure.
  • the concentrated extract was suspended in 2% sulphuric acid (1 Ltr) and partitioned three times with chloroform (3 x 500 ml).
  • the chloroform washings were discarded and the aqueous phase was basified with ammonia solution.
  • the basified aqueous phase was partitioned three times with chloroform (3 x 500 ml).
  • the combined chloroform extract obtained was freed from traces of water by passing through anhydrous sodium sulphate and concentrated under reduced pressure to get solid light brown residue.
  • Potassium iodide (8 grams) was dissolved in water (30 mL). 3. A stock solution was prepared by mixing Solution A and Solution B in 1 : 1 ratio. Stock solution (1 mL) was mixed with glacial acetic acid (2 mL) and water (10 L).
  • vasicine reference standard (2 mg) was weighed accurately and transferred to a 5 mL volumetric flask. Then methanol (AR Grade) (3.0 mL) was added and sonicated in an ultrasonic water bath until it dissolved. The volume was made up with methanol.
  • a ethyl p-methoxycinnamate reference standard (2 mg) was weighed out and transferred to a 5 mL volumetric flask.
  • Methanol (AR Grade) (3.0 mL) was added and sonicated in an ultrasonic water bath until it dissolved. The volume was made up with methanol. The aliquotes of the resulting solution were used as reference standard solution for ethyl p- methoxycinnamate.
  • Adhatoda extract 500 mg was weighed out and transferred to a 50 mL conical flask. Methanol (10 mL) was added to and sonicated in an ultrasonic water bath for 10 minutes. After sonication, the conical flask was heated to a boil for a few seconds. The contents of conical flask were filtered through a Whatman No.41 filter paper. The resulting solution was used as a test solution.
  • Hydechium extract 500 mg was weighted and transferred to a 50 mL conical flask.
  • Methanol (10.0 mL) was added to and sonicated in an ultrasonic water bath for 10 minutes. After sonication, the conical flask was heated to a boil for few seconds. The contents of the conical flask was then filtered through a Wliatman No.41 filter paper. The resulting solution was used as test solution.
  • Curcuma extract 500 mg was weighed out and transferred to a 50 mL conical flask. Methanol (10.0 mL) was added to and sonicated in an ultrasonic water bath for 10 minutes. After sonication, the conical flask was heated to a boil for few seconds. The contents of the conical flask was then filtered through a Whatman No.41 filter paper. The resulting solution was then used as a test solution. e) Procedure
  • the chloroform layer was discarded.
  • the aqueous layer was basified with a dilute ammonia solution (up to pH 9-10) and was extracted four times with each of the 100 mL of chloroform.
  • the chloroform layers were collected and passed over an anhydrous sodium sulphate.
  • the chloroform layer was evaporated in a pre- weighed beaker to dryness on a water bath.
  • the beaker was dried in an oven for 1 hour at temperature 105°C.
  • the beaker was cooled in a descicator and the weight was noted.
  • the total alkaloid content should be from about 0.005%> to about 25%.
  • Invert sugar syrup was transferred to a steam jacketted kettle and warmed to 45-50°C. To this, extract solution was added and mixed well for 15-20 minutes. A preservative solution was added to the syrup and mixed well for 10-15 minutes. The pH of the syrup was checked. Flavor was added to the syrup and mixed well for 15-20 minutes and final volume was made up with purified water and again mixed well. The syrup is filtered through a size #100 mesh nylon cloth and transferred to a storage tank. EXAMPLE 8 Detection and Quantification Of Vasicine From The Syrup
  • Wavelength for recording the chromatogram 292 nm
  • Application volume 5 and 10 ⁇ L of reference standard and 10 and 20 ⁇ L of test sample
  • vasicine 25 mg was dissolved in methanol (25 mL) by sonication and heating. The resulting solution was used as a reference standard solution for vasicine. Preparation of test solution
  • 1,4- dioxane AR 25 mL
  • toluene AR 0.1 L
  • methanol and ammonia solution 0.5 mL
  • Tins solution was sonicated for 2-3 minutes and 20 mL was then transferrerd to a 10x10 cm HPTLC chamber. The HPTLC chamber was saturated for 30 minutes.
  • the plate was scanned at ⁇ max 292 nm using deuterium lamp and the content of vasicine was calculated in the product.
  • EXAMPLE 9 Detection and Quantification Of Ethyl P-Methoxycinnamate from the Syrup Instrument: Camag's High Perfo ⁇ nance Thin Layer Chromatographic system equipped with Linomat V and photo documentation unit.
  • Wavelength for recording the chromatogram 310 nm
  • Application volume 5 and 10 ⁇ L of reference standard and 10 and 20 ⁇ L of test sample
  • Ethyl p-methoxycinnamate (25 mg) was dissolved in methanol (25 mL). The resulting solution was used as a reference standard solution for ethyl p-methoxycinnamate.
  • N-hexane AR (80 mL) and Acetone AR (20 mL) were measured using the same measuring cylinder and transferred to a 100 mL stoppered conical flask. The flask was sonicated for 2-3 minutes for proper mixing and approximately 20 mL was transferred to a 10x10 cm HPTLC chamber. The HPTLC chamber was saturated for 30 minutes.
  • the plate was scanned at ⁇ max 310 nm using a deuterium lamp.
  • the content of ethyl p- methoxycinnamate was calculated in the product.
  • the % content of ethyl p-methoxycinnamate is calculated by the formula below: x x 100 ASTD D SPL
  • a SPL Area of sample corresponding to ethyl p-methoxycinnamate.
  • a S T D Area of ethyl p-methoxycinnamate D
  • S T D Dilution of reference standard solution D
  • D SPL Dilution of test sample

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Abstract

La présente invention a trait à une nouvelle préparation pharmaceutique à base d'herbes médicinales pour le traitement et le contrôle de la toux. La préparation pharmaceutique à base d'herbes médicinales comporte des extraits d'Adhatoda, d'Hedychium et de Curcuma ou un mélange de principes actifs extraits de ces herbes avec des supports et/ou diluants pharmaceutiquement acceptables. L'invention a également trait à des procédés pour la fabrication de préparations pharmaceutiques et l'isolement, l'identification et l'analyse quantitative de substances phytochimiques individuels utilisés dans les préparations à base d'herbes médicinales.
PCT/IB2005/000136 2004-01-19 2005-01-19 Preparation a base d'herbes medicinales comportant des extraits d'adhatoda, d'hedychium et de curcuma comme sirop contre la toux WO2005077393A1 (fr)

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WO2007046113A3 (fr) * 2005-10-18 2007-07-26 Panacea Biotec Ltd Composition pharmaceutique renfermant un ou plusieurs alcaloides et procede
WO2008010697A1 (fr) * 2006-07-19 2008-01-24 Herrera Ramirez Mario Alberto Médicament à base de curcumine servant à traiter une infection parasitaire provoquée par giardia lamblia
WO2011087393A1 (fr) * 2010-01-18 2011-07-21 Общество С Ограниченной Ответственностью "Вегавольт" Composition d'origine végétale destinée à l'inhalation de la fumée générée par sa combustion
CN105412744A (zh) * 2015-12-04 2016-03-23 海南葫芦娃制药有限公司 一种麻龙中药组合物的应用
US9517249B2 (en) 2012-11-26 2016-12-13 Access Business Group International Llc Antioxidant dietary supplement and related method
KR20170139488A (ko) * 2015-05-06 2017-12-19 이아이디 패리 (인디아) 리미티드 개선된 식물 성장을 위한 생물자극제 조성물 및 이의 제조방법

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007046113A3 (fr) * 2005-10-18 2007-07-26 Panacea Biotec Ltd Composition pharmaceutique renfermant un ou plusieurs alcaloides et procede
WO2008010697A1 (fr) * 2006-07-19 2008-01-24 Herrera Ramirez Mario Alberto Médicament à base de curcumine servant à traiter une infection parasitaire provoquée par giardia lamblia
WO2011087393A1 (fr) * 2010-01-18 2011-07-21 Общество С Ограниченной Ответственностью "Вегавольт" Composition d'origine végétale destinée à l'inhalation de la fumée générée par sa combustion
US9517249B2 (en) 2012-11-26 2016-12-13 Access Business Group International Llc Antioxidant dietary supplement and related method
US10201583B2 (en) 2012-11-26 2019-02-12 Access Business Group International Llc Antioxidant dietary supplement and related method
KR20170139488A (ko) * 2015-05-06 2017-12-19 이아이디 패리 (인디아) 리미티드 개선된 식물 성장을 위한 생물자극제 조성물 및 이의 제조방법
US20180153175A1 (en) * 2015-05-06 2018-06-07 Eid Parry (India) Limited Bio-stimulant composition for improved plant growth and the process of preparing the same
US10624352B2 (en) * 2015-05-06 2020-04-21 Coromandel International Limited Bio-stimulant composition for improved plant growth and the process of preparing the same
US11122809B2 (en) 2015-05-06 2021-09-21 Coromandel International Limited Bio-stimulant composition for improved plant growth and the process of preparing the same
KR102565972B1 (ko) 2015-05-06 2023-08-10 이아이디 패리 (인디아) 리미티드 개선된 식물 성장을 위한 생물자극제 조성물 및 이의 제조방법
CN105412744A (zh) * 2015-12-04 2016-03-23 海南葫芦娃制药有限公司 一种麻龙中药组合物的应用

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