WO2002026226A1 - Pharmaceutical composition of dihydroartemisinin for treating malaria - Google Patents

Abstract

The present invention provides a composition for treating malaria, comprising dihydroartemisinin, piperaquine and trimethoprim as well as their analogs and salts. Said compositions exhibit therapeutic action rapidly with high efficiency and low toxicity in animal models and clinical tests. The period of treatment when administrating the composition above is much shorter than that when using other antimalarials. The composition according to the invention contains dihydroartemisinin and piperaquine as the essential principles which are demonstrated to be synergetic.

Description

 Technical field of dihydroartemisinin for treating malaria

 The present invention relates to a hydroartemisinin pharmaceutical composition for treating and preventing mammals, especially human malaria and other types of malaria.

Background technique

 Multidrug-resistant malaria is spreading globally, with Africa and Southeast Asia particularly severe. The World Health Organization has included "malaria control" as one of the important plans for the 21st century. There was great hope for Mefloquine and its complex method, Simimef. However, due to the rapid emergence of drug resistance, first in Thailand and then in Vietnam, it is already in a state of very poor efficacy and low toxicity ( Guoqiao Li and others used Fansimef to treat falciparum malaria at Xuan Loc Hospital in Vietnam, with a cure rate of 55%, unpublished data 1995). Artemisinin and its derivatives artesunate, artemether, artemether, dihydroartemisinin, etc., which have been developed and invented since the 1970s in China, have the advantages of high yield and rapid effect, but must be taken for 7 days to achieve a high cure rate. Otherwise, the re-ignition rate is high, which is not conducive to the control of malaria infection sources.

 A technical compound artemether (composed of artemether and phenethyl alcohol) purchased by Swiss NORVATIS pharmaceutical company from China may be better than existing antimalarial drugs, but its treatment still takes 3 days and is relatively costly. Malarone, which is being developed by Glaxo Wellcome in the United Kingdom, is composed of naphthoquinone and cyclochloroguanidine. There is no fast-acting drug in its formula. The course of treatment is 3 days, twice a day, and the cost is high. If the dosage is changed to once a day, nausea and vomiting have serious side effects.

Summary of the Invention

 The object of the present invention is to provide a new dihydroartemisinin pharmaceutical composition for fast-acting, high-efficiency, low-toxicity and short-course treatment of malaria, especially multi-drug-resistant malaria.

 The composition of the present invention contains (1) dihydroartemisinin as a therapeutically active ingredient

(dihydroartemisinin), and / or its analogs and salts, and (2) pie (piperaquine) and / or its analogs and salts; and pharmaceutically acceptable carriers. Optionally, the composition of the present invention further contains (3) trimethoprim (Trimethoprim), and / or its analogs and salts as a therapeutically active ingredient.

 The content of the active ingredients is such that their combination is effective for treating malaria.

 Preferably, the ratio of each active ingredient in the composition of the present invention is as follows:

 Hydroartemisinin, and / or its analog and salt 1 part

 Quine, and / or its analogs and salts 3 to 7 parts of trimethoprim, and / or its analogs and salts 0 to 5 parts The optimal weight (parts) ratio of the drug of the present invention is:

 Dihydroartemisinin, and / or its analog and salt 1 part

 Piperazine, and / or its analogs and salts 5 servings

 Trimethoprim, and / or its analogs and salts 2.5 parts

 The medicine of the present invention may also be a compatible preparation of dihydroartemisinin and piperazine. The weight (parts) ratio is:

 Dihydroartemisinin, and / or its analog and salt 1 part

 Piperazine, and / or its analogs and salts 6 servings

 The analogs of dihydroartemisinin in the composition of the present invention are artemisinin and its derivatives, such as artemisinin, artesunate, artemether, and arteether. Such drugs are eventually converted into dihydroartemisinin in the body and exert their killing effect on malaria.

Analogues of piperquine in the composition of the present invention include: 4-aminoquinoline derivatives such as chloroquine (Chloroquine), aminophenol ¹ : (Amodiaquine), and the like.

 Analogs of trimethoprim in the composition of the present invention include: Co-Trimoxazole / Bactrim and the like.

The salt of the active ingredient according to the present invention refers to a non-toxic base salt formed by an acidic compound and a pharmaceutically acceptable base, or a non-toxic acid addition salt formed by a basic compound and a pharmaceutically acceptable acid. The non-toxic base salts include, but are not limited to, from pharmaceutically acceptable cations such as Alkali metal cations (such as potassium and sodium) and alkaline earth metal cations (such as calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine (glucamine) and lower alkanolammonium derived salts And other pharmaceutically acceptable organic amines. The non-toxic acid addition salt refers to a non-toxic acid addition salt formed by a compound and an organic or inorganic acid. I.e. salts containing pharmacologically acceptable anions such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate , Citrate, acid citrate, tartrate, tartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, mesylate Salts, ethanesulfonic acid salts, benzoic acid salts, p-toluenesulfonate and naphthenate.

 The above-mentioned solution of the present invention is based on the understanding of the pathogenesis of malaria and the principles of treatment in Chinese medicine, and refers to the achievements of modern pharmacological research, that is, the principle of the formula of the present invention is, but not limited to: Dihydroartemisinin has Fast-acting, low-toxicity, can quickly and massively kill the drug-resistant P. falciparum, but if the drug is not taken continuously for 7 days, the re-ignition rate is high; piperquine has long-acting and synergistic characteristics, which can shorten the treatment period to 2 days; Make up for the deficiency of dihydroartemisinin; trimethoprim is a synergist, which helps to improve the cure rate and reduce the re-ignition rate. Dihydroartemisinin can delay the emergence of resistance to piperazine and trimethoprim.

The drug of the present invention has undergone pharmacodynamics, toxicology, general pharmacological tests and clinical research, as well as preparation technology, quality testing and stability investigation, etc., and has curative effects on malaria in China's Hainan Province and Vietnam, Thailand, and Cambodia in areas where drug-resistant malaria is endemic. experimenting. The results of the study prove that its efficacy on malaria, especially multi-drug-resistant malaria, is superior to any existing anti-malarial drugs. It can be used to treat malaria, psoriatic malaria, and other types of malaria. It is by far the world's highest cure rate for malaria , New insecticide with fast insecticidal speed, low toxicity and side reaction, high safety, single process cartridge, mature and good stability. Piperazine used in the existing treatment methods is usually used in its phosphate form, and one of the main components of the composition of the present invention can also be used without its phosphate form, which reduces the dosage, reduces side effects, and reduces costs. . The biggest feature of the composition of the present invention is that Then, it only takes 2 days to cure. The actual application value is great.

 The pharmaceutical preparation of the present invention refers to the above-mentioned hydroartemisinin, piperquine and the like, and the salts thereof, with or without trimethoprim as a synergist according to different therapeutic uses, and controlling each active ingredient in the Within the specified ratio range, combined with known pharmaceutical preparation technology and acceptable excipients or carrier substances at the pharmaceutical level, it is made into a solid by the usual known preparation production methods such as pulverization, mixing, dissolving, tabletting and coating. Or liquid preparations, such as tablets, capsules, granules, suppositories and injections.

 The pharmaceutically acceptable carrier according to the present invention refers to a pharmaceutically acceptable carrier that does not affect the activity of each active ingredient and has no toxic or side effects on the human body. The composition of the present invention can be formulated for oral administration, such as an emotional diluent or an assimilated edible carrier, or it can be encapsulated in a hard or soft shell capsule, or it can be compressed into tablets. For gastrointestinal administration, the active compound can be combined with excipients in ingestible tablets, pills, buccal tablets, granules, dragees, capsules, tinctures, suppositories, syrups, Glutinous rice paper tincture and other dosage forms are used. Such compositions and preparations should contain at least 1% by weight of active compound. The percentages of the compositions and preparations may, of course, be different, and are preferably between about 5 and about 80% by weight. The amount of active compound in this therapeutically useful composition makes it possible to obtain suitable dosages. After preparation of a preferred composition or formulation according to the present invention, an oral unit dosage form contains from about 50 mg to about 1000 mg of the active compound.

Tablets, lozenges, pills, capsules, etc. may also contain the following components: a binder, such as gum, gum arabic, corn starch, or gelatin; an excipient, such as dicalcium tablet, a disintegrant, such as corn Starch, potato starch, alginic acid, etc .; lubricants, such as magnesium stearate; sweeteners, such as sucrose, lactose, or saccharin, or flavoring agents, such as mint, holly oil, or cherry pick flavoring agents. If the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may also be present as coatings or to alter the physical shape of the unit dosage form. For example, tablets, pills or capsules can be coated with shellac, sugar or both. Syrups or tinctures can contain Active compounds also contain sucrose as a sweetener, methyl paraben and propyl ester as preservatives, and dyes and flavoring agents such as cherry pickle or orange flavoring agents. Any raw material used to prepare any unit dosage form should be pharmaceutically pure and substantially non-toxic at the dosages used. In addition, the active compound may be incorporated in a sustained-release preparation.

 Compositions suitable for injection use include sterile aqueous solutions (as long as they are water soluble) and sterile powders for the temporary preparation of sterile injectable solutions. They must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium, for example, containing water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils. The use of various antibacterial and antifungal agents can prevent the effects of microorganisms, such as parabens, chlorobutanol, phenol, sorbitol, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride.

 Sterile injectable solutions are prepared by mixing the required amount of various active compounds in a suitable solvent with a variety of other ingredients listed above, and then sterilizing by filtration or other appropriate means, if necessary . Dispersions are also targeted by the present invention. They can be prepared by incorporating a variety of sterile active ingredients into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders used in the preparation of sterile injectable solutions, the preferred method of preparation includes vacuum drying and freeze drying techniques to obtain a powder of the active ingredient plus any additional required ingredients, the additional ingredients from the previous sterile filtration The solution.

 Pharmaceutically acceptable carriers and / or diluents include any of all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of these media and agents for pharmaceutically active substances is well known in the art. Except incompatible with the active ingredient within the scope of conventional media or agents, the present invention is directed to its use in therapeutic compositions.

It is particularly advantageous to formulate unit dosage forms for oral compositions for easy administration and uniform dosage. The unit dosage form used herein refers to physically discrete units, suitable as A single dose is used for treatment; each unit contains a predetermined amount of active substance associated with the desired pharmaceutical carrier, and the content is calculated to produce the desired therapeutic effect. The description of the unit dosage form of the present invention depends on and directly depends on (a) the unique properties of the active substance and the specific therapeutic effect to be achieved, and (b) the limitations inherent in the field of formulation.

 The effective amount targeted by the present invention will vary depending on the severity of the disease and the health condition and age of the subject. Factors such as the size of the active ingredient used, the dosage form and the route of administration should also be considered. Generally, the composition of the present invention is administered at 20 mg-300 mg (the other active ingredient is calculated according to the aforementioned ratio) based on hydroartemisinin every day, and the effect can be seen in 2 days.

 The pharmacodynamic research on rat malaria and monkey malaria has shown that the dihydroartemisinin composition of the present invention has significant synergistic effects. The inventors conducted clinical trials in China, Vietnam, and Cambodia using the dihydroartemisinin examples of the example, and clinical studies have shown that they have a high cure rate for malaria. Treatment of 975 cases of falciparum malaria, follow-up observation for 28 days, cure rate of 96.9%, relapse rate of 3.1%, treatment of 171 cases of vivax malaria, same follow-up observation of 28 days, recurrence rate of 2.7%, can quickly control clinical symptoms. The average antipyretic time is 16-25 hours, and the average protozoan time is 24-56 hours. The dose of hydrogen artemisinin can kill more than 95% of Plasmodium falciparum in 24 hours.

 Random comparisons with the dihydroartemisinin composition of Example 1 include: mefloquine 1250mg, cure rate 82.5%; Fansimef 3 tablets, cure rate 82.9%; artesunate 600mg / 5 days, cure rate 66.2%; A Fluoroquine 750mg + artesunate 150mg, the cure rate was 70.7%.

The present invention also uses hydroartemisinin, piperazine and the composition of the present invention to compare the therapeutic effects, and the results are as follows: Table 1: Clinical comparison results of the dihydroartemisinin composition of the present invention with dihydroartemisinin and piperazine

本发明的最佳实施方式

Best Mode of the Invention

 Further features of the invention are described more fully in the following examples. It goes without saying, however, that the purpose of including these detailed descriptions is merely to exemplify the present invention. The embodiments should not be construed as limiting the broad description of the invention described above in any way.

 Example 1: Production of 1000 tablets of the drug of the present invention, the amount of which was measured according to the following formula: Dihydroartemisinin 75g

 Piperquine 375g

 Trimethoprim 187.5g

Hydroxypropyl cellulose _35g

 The raw and auxiliary materials are tested first, and after crushing and passing through a 100-mesh sieve, the components are accurately measured according to the formula, and the components are mixed and uniformly granulated, tabletted, and packed.

The method and dosage of the drug in this embodiment: One course of treatment for an adult is 2 days, and the total dose of the course of treatment is 300 mg of dihydroartemisinin, 1.5 g of piperazine, and 750 mg of trimethoprim. The administration method is 0 hours, 8 hours, 24 hours, and 32 hours, 1 tablet each time (ie, dihydroartemisinin 75 mg, piperazine 375 mg, and trimethoprim 187.5 mg). After more than 500 clinical trials It proves that this drug has the characteristics of fast-acting, high-efficiency, low-toxicity and short course of treatment, and its efficacy is obviously better than similar drugs at home and abroad. Example 2: To produce 1000 tablets of the drug of the present invention, take the following formula:

 Hydroartemisinin 50g

 Piperquine 250g

 Manufacturing method is the same as in Example 1. Administration and dosage: Orally. Adults take 2 tablets twice daily (100 mg dihydroartemisinin and 500 mg pacliquine) for 2 days. Example 3: Formula for producing 1000 bags of compound dihydroartemisinin granules:

 Artemether 20g

 Piperazine phosphate 160g

 Trimethoprim 60g

 Sucrose powder 200g

 300g starch

 Hydroxypropyl cellulose 50g

Lemon yellow 0.5 _g

 It is prepared according to the usual method for the production of pharmaceutical granules and is intended for children under 7 years of age, each containing artemether 20mg, piperazine phosphate 160mg, and trimethoprim 60mg.

 Each course Method and dosage: Take cold water to make a paste orally. (Unit: bag) Age (years) First dose 6 hours 24 hours 32 hours

 4 ~ 7 3/2 3/2 3/2 3/2

2 ~ 4 1 1 1 1

 <2 1/2 1/2 1/2 1/2 Example 4: Production of compound dihydroartemisinin suppositories 1000 capsules, according to the following formula:

Dihydroartemisinin 85g Piperazine phosphate 500g

 Trimethoprim 160g

 Lanolin 100g

 Glycerin 200g

 Paraffin 200g

 According to the conventional method of suppository preparation, each suppository contains 85 mg of dihydroartemisinin, 500 mg of piperazine phosphate, and 160 mg of trimethoprim for rectal administration, 1 capsule 2 times a day. 4 capsules per course. Example 5: Formulation example of the injection of the present invention, made into 1000 succinate piperazine injections:

 Artesunate 100g

 Piperquine 500g

 Soybean oil for injection 800ml

 5g sodium sulfite

 Polyethylene glycol 10ml

 For injection. Adults inject once a day and increase the amount by 1/2 for the first time (ie artemisinate 150 mg, paequine 750 mg). One course of injection for two days. The total amount is 250mg artesunate and 1250mg piperazine. Example 6: According to the ointment formulation of the present invention for rectal administration of children, 1000 compound dihydroartemisinin ointments were prepared according to the usual process of ointment:

 Hydroartemisinin 50g

Quinolin 250g

Trimethoprim 140 _g

Beeswax 100g

Medical Vaseline 200g 40g glyceryl monostearate

 For children with severe symptoms, when oral administration is difficult, rectal perfusion is used for treatment. Each ointment contains 50mg dihydroartemisinin, 250mg piperazine, and 140mg trimethoprim, twice a day, one at a time for two days. Industrial applicability

 The invention provides a dihydroartemisinin composition for treating malaria, which can be used for preparing a pharmaceutical preparation for treating malaria. Animal tests and clinical tests have shown that the composition of the present invention has the characteristics of fast-acting, high-efficiency, low cost, low toxicity, short treatment course, and its curative effect and low toxicity and side effects are obviously better than similar products at home and abroad.

Claims

Rights request 1. A hydroartemisinin composition for treating malaria, which contains as a therapeutically active ingredient:  (1) dihydroartemisinin, and / or its analogs and salts,  (2) piperazine, and / or its analogs and salts, And pharmaceutically acceptable carriers.  2. The composition according to claim 1, further comprising as a therapeutically active ingredient:  (3) trimethoprim, and / or its analogs and salts.  3. The composition according to claim 1 or 2, wherein the proportion of each active ingredient is: dihydroartemisinin, and / or its analog and salt 1 part  Piperquine, and / or its analogues and 3 to 7 parts trimethoprim, and / or its analogues and salts 0 to 5 parts  4. A composition according to claim 3, comprising:  Hydroartemisinin, and / or its analog and salt 1 part  Piperazine, and / or its analogs and salts 5 servings  Trimethoprim, and / or its analogs and salts 2.5 parts  5. The composition according to claim 3, comprising:  Dihydroartemisinin, and / or its analog and salt 1 part  Piperazine, and / or its analogs and salts 6 servings  6. The composition according to claim 1 or 2, wherein the analogues of dihydroartemisinin are artemisinin, artesunate, artemether, artemether.  7. The composition according to claim 1 or 2, which is prepared in the form of a pharmaceutical preparation, wherein the preparation includes a tablet, a capsule, a suppository, a granule, and an injection.  8. Use of a composition according to claims 1 to 6 for the manufacture of a medicament for the treatment of malaria.