JP2946452B2 - Composition containing piperine - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to pharmaceutical compositions with increased therapeutic efficacy. In particular, the invention relates to compositions comprising piperine as a bioavailability enhancer. The composition of the present invention is useful for treating diseases affecting the human cardiovascular system, central nervous system, gastrointestinal system, respiratory system, endocrine system, genitourinary tract, blood generating system, etc. is there.

[0002]

BACKGROUND OF THE INVENTION While many drugs are available on the market for treating diseases affecting these systems, there are affordable and effective non-toxic drugs for treating those diseases. Putting it in is useful. Therefore, research is underway to develop these drugs in an effort to define dosage forms and improve composition by finding the smallest possible dose that effectively controls those diseases. In this regard, the bioavailability of specific drugs for treating disease is being exploited to develop effective and inexpensive drugs.

In the medical field, complex compositions are commonly used to treat many of the above diseases. In such compositions, it is known to use certain herbs or herbs in combination or alone to enhance the therapeutic effect of the active drug. There are many reports that such drugs are used in combination with other drugs to enhance the efficacy and therapeutic efficacy of the drug. Whether these herbs have unique properties to cure various diseases, or
It is not clearly understood that it plays a role other than helping to cure the disease.

[0004] A great deal of research has been done to determine this. Dat U. C. And King G. Describe their herb-containing compositions in their paper (1900) published at Materia Medica, Hindus, Calcutta. Laxmi Pachi A. Is the third edition of Madras's Arogya Ashram Samichi's "Hundred Useful Drugs"
In their paper entitled (1946), these herbs were reported to be useful in regulating the balance of Kapha, Vata and Pitta. According to Ayurvedic experts, Kapha, Vata, and Pitta are three bodily fluids whose imbalance causes disease. Bowes K. G. FIG.
In their paper (1928), published at Pharmacopia Indica, Calcutta, demonstrated that the properties of long pepper that enhances the efficacy of the anti-asthmatic drug Vasaka are correct.

[0005] Herbs, especially Trikatsu (Trikatu)
s) Studies on the basis of the widespread use of herbs belonging to the group have been carried out on scientific grounds. Usha Zucci et al. Published their papers in Indian Drugs (1982, (12), 476-479).
Reported the effect of trichat, which acts on Vasicine as a whole and greatly enhances the bioavailability of the drug. They also say that Piper Longum (P
iper longum) and Piper nigurum (Pip
er.nigrum is almost equally effective, whereas ginger (Zingiber-Offi)
It was observed that C. cinalis alone had no significant effect.

[0006] Indian Patent Application No. 1232 / DEL / 89 of the Scientific and Industrial Research Society of New Delhi, India, discloses piperine for the treatment of tuberculosis and / or leprosy known antituberculosis and / or antileprosy disease. A method is described and claimed that, in combination with a drug, such a combination confers a synergistic synergistic effect on the anti-tuberculosis and / or anti-leprosy agent that results in enhanced therapeutic efficacy. I have.

A piperine represented by the formula (1) shown in the present specification,
(EE) 1- [5,3-benzodioxyl-5-
Il) -1-Oxo-2,4-pentadienyl] -piperidine is a major component of many pepper species.
It is generally grown on a large scale in India and is therefore readily available for Piper Longum (3-5%)
Alternatively, it is obtained from Piper nigrum (3-9%). Piperine forms a monoclinic column from an ethanol melting point of 130 ° C. It is tasteless at first, but causes a tingling sensation after a few seconds. It is soluble in benzene, chloroform, ether, ethyl acetate, dichloromethane, alcohol, acetic acid, but not in water or petroleum ether.
Upon alkaline hydrolysis, it becomes the base piperidine and the acid, ie, piperic acid, mp 216 ° C.

[0008] IR (KBr): 2930,163
3,1610,1580,1510,1440,125
0,1190,1130,1030,995,930,
842 cm @ -1. 1H NMR, CDCl3 ref TMS: 1.6
2 (6H, bs, 3xCH2), 3.49 (4H, b
s, 2xNCH2), 5.92 (2H, s, O-CH2-)
O), 6.38 (d, J = 15 Hz, -CC = C
−), 6.72-6.92 (6H, m, 3 olefi)
nic & 3 Ar-H), 7.25-7.51 (1
H, m, -CC = C-).

13C NMR (CDC13): 138.4
(C-1), 113.0 (C-2), 155.5 (C-
3), 155.5 (C-4), 115.0 (C-5),
129.8 (C-6), 145.4 (C-7), 13
2.6 (C-8), 149.6 (C-9), 127.5
(C-10), 172.6 (C-11), 50.8 (C
-1 '), 33.3 (C-2'), 31.9 (C-
3 '), 33.3 (C-4'), 53.8 (C-
5 '), 108.6 (C-6') MS (%): M + 285 (13.6), 200 (1
00), 172 (42.5), 142 (31.0), 1
14 (75.1), 84 (32.51).

[0010] Piperine is Piper Nigrum (black pepper)
Alternatively, it can be separated from the oil-containing resin of Piper Longum (long pepper). The powdered fruit of the plant (P. nigurum)
Extract with dichloromethane at room temperature with stirring for 12 hours. The extract is filtered and condensed in vacuo, and the residue is purified on an alumina column. Pure piperine
It can be obtained from ethanol by crystallization. Piperine can also be obtained in smaller quantities directly from the raw residue by extraction with alcohol, filtration and subsequent crystallization. The above patent application (Indian application 1232 / DEL)
/ 89), studies were continued to find the reason for the synergistic effect of piperine with antituberculosis and / or antileprosy agents.

As a result of our constant research work, we have found that the reasons for such a selective mode of action of piperine may be due to the following points. i) synergistic properties that increase the absorption of certain drugs; the present invention is particularly useful in the absorption of such drugs through the gastrointestinal membranes of the human body. ii) The role of using piperine together with the drug so that the drug does not disappear from the human body, and keeping the drug in the human body for a longer time. iii) the ability to increase the binding of serum proteins, thereby retaining most of the drug in combination with piperine in the human body for a longer time. iv) properties that stimulate the body's natural immune system to enhance the production of antibodies against microbial infections.

[0012]

EXAMPLES Based on the above findings, the present inventors continued their research to determine the effects of piperine, which when used in combination with piperine, enhance and / or modify the bioavailability of the drug. That is, the present inventors have the formula

Embedded image Piperine and antimicrobial, antiprotozoal, anthelmintic, cardiovascular, central nervous, nonsteroidal anti-inflammatory, respiratory, antihistamine, prokinase-like, cortico Attempts to combine steroids, steroid hormones, oral vaccines, blood boosters, vitamins, anti-ulcer drugs, muscle relaxants and anti-cancer drugs.

Our research work has revealed that the synergistic effect of the combination of piperine is not limited to antituberculosis drugs and antileprosy drugs. The effect also creates a synergistic activity that enhances the bioavailability of certain other drugs. We have found that the bioavailability of the agents listed below is also enhanced by their synergistic effect when used in combination with piperine. 1. Antimicrobial agents such as ciprofloxacin pefloxacin cephalexin roxithromycin cefixime

2. 2. Antigenic animal drugs such as metronidazole tinidazole quinine chloroquine primaquine sulfadoxine + pyrimesamine 3. Mebendazole to anthelmintic H cysts such as: Cardiovascular drugs such as amlodipine diltiazem atenolol lisinopril lovastatin gemfibrozil nifedipine enalapril propanolol

[0015] 5. 5. Drugs acting on the central nervous system such as L-dopa buspirone dextropropoxyphene pentazocine morphine derivative diazepam lorazepam alprazolam haloperidol chlorpromazine thioridazine Non-steroidal anti-inflammatory drugs such as diclofenac ketorolac piroxicam ibuprofen indomethacin naproxen

[7] Used to treat respiratory disorders such as:
Drug Sorubitamoru terbutaline theophylline bromhexine 8 to be. 8. Antihistamines astemizole terfenadine loratadine as follows Prokinase- like drugs metoclopramide domperidone cisapride

10. 10. Corticosteroid prednisolone dexamethasone betamethasone as follows: 11. Steroid hormone stazolol, oral contraceptives such as: 12. vaccine oral polio such as Blood boosters / ferrous vitamin / ferric iron containing drugs, multivitamin preparations such as: 14． The following anti-ulcer drugs: omeprazole ranitidine femotidine and the like. 15. Central muscle relaxants calisoprodol chlormezanone

16. Anticancer drug (i) Alkylating agent such as mechlorthiamine cyclophosphamide ifosamide chlorambucil hexamethylmelamine thiotepa busulfan carmustine lomustine semustine streptozotocin decarbazine

(Ii) Antimetabolites methotrexate 5-fluorouracil floxyuridine cytosine arabinoside 6-mercaptopurine thioguanine pentostatin

(Iii) The following natural products: vincristine vinblastine etoposide teniposide deotinimycin daunorubicin doxorubicin epirubicin idarubicin bleomycin mythramycin mitomycin L-asparaginase interferon alpha

(Iv) Various drugs cisplatin carboplatin mitoxantrone hydroxyurea procarbazine mitotane aminoglutethimide

(V) Hormones and hormones such as:
Antagonist Prednisolone Hydroxyprogesterone Medroxypprogesterone Megestrol Diethylstilbestrol Ethinyl Estradiol Tamoxifen Testosterone propionate Fluoxymesterone Flutamide Leuprolide

The present invention also provides a compound of the formula

Embedded image Of a medicinal composition having enhanced therapeutic efficacy comprising piperine. The drug mix is based on the human cardiovascular, central nervous, gastrointestinal, respiratory, endocrine,
This is done by mixing the drug used for treatment of the genitourinary or blood-forming system with piperine.

In a preferred embodiment of the present invention, the amount of piperine used may vary from 0.1 to 50% by weight of the drug. More preferably, the amount of piperine is
It may vary from 0.1 to 20% by weight of the drug. The amount of drug in the composition may vary from 70 to 95% by weight of the composition. The remaining 30 to 5% of the composition is composed of piperine and, as a necessary pharmaceutically acceptable inert excipient, excipients, diluents and / or binders.

Although the efficacy of the composition is more effective when piperine and the drug are administered in a single composition, the possibility of administering the drug and the required amount of piperine separately is also an aspect of the present invention. According to it. In other words, the drug and piperine may be administered separately to the patient. However, it is preferred that the composition be used in a single dosage form. The composition is preferably administered orally. If the drug and piperine are administered separately, they are preferably administered orally. The drug used in the composition may be any one or more of the above drugs.

Piperine is as described above,
No pharmaceutical or pharmaceutical properties. It is therefore surprising that piperine provides a synergistic effect that enhances the bioavailability of the drug. When mixed with the above drugs, piperine produces a synergistic effect, resulting in a composition that enhances the bioavailability of the drug, thereby reducing the amount of drug that must be administered to the patient to achieve the same therapeutic effect. It is observed from the above that it helps. Such effects avoid unnecessary administration of the drug to the patient, which helps to minimize, reduce, or eliminate any adverse effects that the drug may have on the patient. . In other words, such a composition
Increase the therapeutic index of the drug. Thus, the combination of piperine with any one or more of the above agents is not a mere admixture of components employed in a method that results in a mere aggregation of component properties.

[0027] The pharmaceutical composition prepared by the method of the present invention may be in any form normally employed for administering drugs for therapeutic purposes. That is, the composition is:
It may be in the form of tablets, capsules, syrups, liquid suspensions, elixirs, caplets, powders, chewables, wafers, sweetened tablets, external preparations, salves and the like. The composition also comprises
Flavoring, coloring and / or sweetening agents may be included.

The present invention will be described in detail by way of the following examples, which are provided merely by way of example, but it should be understood that the following examples are not intended to limit the scope of the invention. Example 1 Composition Ciprofloxacin 250 mg Piperine 5 mg Dosage form: Hard gelatin capsule Formulation Formulation Pharmacopoeia criteria The method was adopted for the analysis of ciprofloxacin to confirm its purity and potency. In all respects the drug was found to meet the standards of the pharmacopeia. Various analytical methods such as physical, chemical and chromatographic (including TLC and HPL) were employed to assess the purity of piperine as a single entity. Ciprofloxacin and piperine were refined and then blended. Thereafter, the two components were repeatedly sieved and mixed to obtain a uniform mixture. Reproducible analysis was used as a method to confirm the homogeneity of five random samples of the mixture. The formulation was encapsulated in hard gelatin capsules using a manual capsule filling machine. Clinical Trial Methods A controlled clinical trial was performed on 12 healthy volunteers to compare the bioavailability of two formulations containing ciprofloxacin (one containing piperine and the other not). It has been found that the addition of piperine enhances blood levels of the active ingredient ciprofloxacin.

[0029]

[0030]

[0031]

[0032]

[0033]

[0034]

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/495 601 A61K 31/495 601 31/545 601 31/545 601 31/70 613 31/70 613 C07D 215/56 C07D 215 / 56 501/22 107 501/22 107 114 114 114 C07H 17/08 C07H 17/08 B (56) References Indian Patent 172690 (IN, A) Indian Patent 172689 (IN, A) (58) Field of Investigation (Int .Cl. ⁶ , DB name) C07D 317/60 A61K 31/445 CA (STN) REGISTRY (STN)

Claims (3)

(57) [Claims] [Claim 1] Chemical formula A composition comprising piperine and an agent for treating a disease or disorder in a human, wherein the agent comprises ciprofloxacin (Ciprofloxacin).
cin), pefloxacin (Pefloxacin),
A composition selected from the group consisting of cephalexin, roxithromycin, and cefixime, wherein the amount of piperine in the composition is based on the weight of the drug. 0.1 to 50%
A composition wherein the amount of the drug is 70-95% of the composition. 2. The composition according to claim 1, wherein said composition is in the form of a tablet, capsule, syrup, suspension, solution, elixir, caplet, powder, chewable, wafer or sweetened tablet. Item 10. The composition according to Item 1. (3) Chemical formula A composition comprising piperine and an agent for treating a disease or disorder in a human, wherein the agent comprises ciprofloxacin (Ciprofloxacin).
cin), pefloxacin (Pefloxacin),
A composition selected from the group consisting of cephalexin, roxithromycin, and cefixime, wherein the amount of piperine in the composition is based on the weight of the drug. 2. A medicament comprising a composition according to claim 1, wherein the composition is 0.1 to 50% and the amount of the drug is 70 to 95% of the composition.