WO2004026291A1

WO2004026291A1 - Oral formulations of ibuprofen and tramadol, methods and preparation thereof

Info

Publication number: WO2004026291A1
Application number: PCT/CN2003/000713
Authority: WO
Inventors: Shuyi Zhang; Jin Wang
Original assignee: Shuyi Zhang; Jin Wang
Priority date: 2002-08-28
Filing date: 2003-08-25
Publication date: 2004-04-01
Also published as: AU2003264311A1

Abstract

The invention relates to analgesic oral formulations comprising of ibuprofen and tramadol. The formulations are comprising of tramadol or pharmaceutically acceptable salts thereof and ibuprofen or pharmaceutically acceptable salts thereof. The unit dose of above formulations include 80-800mg ibuprofen or pharmaceutically acceptable salts thereof and 12.5-200mg tramadol or pharmaceutically acceptable salts thereof. The invention also disclose the method of preparation of above formulations.

Description

Ibuprofen-tramadol compound oral preparation and preparation method thereof

The invention is a compound oral analgesic preparation composed of ibuprofen and tramadol. Background technique

Opioid alkaloids have been used as analgesics for severe pain for many years. However, because opioid alkaloids can cause a series of adverse reactions, they cannot be given repeatedly or in large doses. Relevant literature has described these side effects in detail, see "The Pharmacological Principles of Therapeutics", 1975, 5th edition, page 245, Chapter 15, by J. Jaffe and W. Martin, L. Goodman and Edited by A. Gilman. The document states that morphine and its analogues, such as codeine, heroin, and hydroxycodeinone, are opioid analgesics and can cause side effects such as respiratory failure, constipation, tolerance, and addiction.

As an alternative to opioid alkaloids, non-opioids such as acetaminophen, aspirin and ibuprofen can also be used for analgesic treatment. Like aspirin, ibuprofen and acetaminophen do not cause opioid analgesics tolerance, addiction, and side effects. However, acetaminophen, aspirin, and ibuprofen can only reduce moderate pain, while opioid analgesics can effectively relieve more severe severe pain. See Pharmacological Principles of Therapeutics, 1975, p. 5 Edition, p. 325, chapter 15, by Woodbury, D. and Fingl, E., edited by L. Goodman and A. Gilman.

In order to reduce the side effects of opioid alkaloids, the combined use of opioids and other drugs containing non-opioid analgesic components can reduce the amount of opioids while achieving the analgesic effect of the original opioid dose. It has been reported that some compound preparations can also produce synergistic analgesic effects. For example, A. Takemori in the Annual Report of the New York Academy of Sciences, 1976, No. 262, p. 281 states that the combination of opioid alkaloids and other non-analgesics can produce a variety of different analgesic effects. , Followed by sub-additive (inhibitory), enhanced or super-enhanced effects. Taber et al., J. Pharra. Expt. Thera., 1969, No. 29, Chapter 169, Section 1, states that a combination of morphine and another opioid analgesic, methadone, can enhance analgesia. effect. U.S. Patent No. 4571400 has disclosed that the two components of the opioid analgesic drug ibuprofen and non-opioid analgesic dihydrocodeine are Compounding within a certain proportion has super analgesic effect. A. Pircio et al. In "Arch. Int. Pharmacodyn.", 1978, No. 116, p. 235 stated that the opioid analgesic butofilol and the non-opioid analgesic paracetamol, namely ΑΡΑΡ : Mixing at a ratio of 125 can be super analgesic, but if mixing at a ratio of 1: 10, there is no obvious super analgesic effect.

Ibuprofen is an anti-inflammatory drug that has been used to relieve pain in humans and animals. Hydrocodone, 7, 8-dihydrocodienone, mainly contains an analgesic and analgesic component, and its effect is similar to that of codeine. The analgesic effect of the compound formulation of ibuprofen and hydrocodone, Vi _CO prof _en ^s , is far better than the analgesic effect of increasing any one of the single medicine amount, US Patent No. 4,587,252. At the same time, the complex is compared with two single drugs at the same analgesic dose, and the former is considered to have less side effects than the latter two.

. Common tablets containing tramadol and paracetamin and methods of use have been patented, US Patent No. 5,336,691. The usual adult dose is 1-2 tablets every 4-6 hours, known as Ul _race t ™. The compound tablet has analgesic and antitussive effects. Summary of the invention

The invention proposes for the first time a new preparation for treating pain in mammals, especially humans, and a preparation method thereof. This method is mainly used for mammals, especially humans, to take a compound formulation composed of tramadol or its pharmaceutically acceptable salt and ibuprofen or its pharmaceutically acceptable salt by the oral route. The technical solution adopted by the present invention to solve the above problems is: the ibuprofen-tramadol compound oral preparation is characterized in that the compound oral preparation contains tramadol or its pharmaceutically acceptable salts and ibuprofen or its pharmacology Compound analgesic pharmaceutical preparations of salts.

The formula according to the present invention comprises a tramadol or a pharmaceutically acceptable salt thereof and ibuprofen or a pharmaceutically acceptable salt thereof. The mass ratio of tramadol and ibuprofen may be between 1: 1 and 1:50.

The formula according to the present invention comprises a tramadol or a pharmaceutically acceptable salt thereof and ibuprofen or a pharmaceutically acceptable salt thereof, and an ideal mass ratio range is between 1: 1 m and 1:20, and the range is 1: 2 The effect is better to 1. · 15. The formula according to the present invention contains (1) 80mg-800mg ibuprofen or a pharmaceutically acceptable salt thereof, (2) 12.5mg-200mg tramadol or a pharmaceutically acceptable salt thereof, and (3) a tablet or capsule is prepared Commonly used medicinal excipients.

The medicinal auxiliary materials according to the present invention may be microcrystalline cellulose, pre-gelatinized starch, sodium starch glycolate, colloidal silicon dihydrate, and magnesium stearate.

The technical solution used by the present invention to solve the above problems is as follows: The method for preparing the ibuprofen-tramadol compound oral preparation is characterized in that: an appropriate amount of tramadol or its pharmaceutically acceptable salts and ibuprofen or its The medicinal salts and necessary medicinal auxiliary materials are mixed in a granulator, and then granulated in water or other liquids, and dried, and the dried granules are ground, and other medicines are added. It is mixed with auxiliary materials, and the lubricated particles can be made into different preparations according to requirements.

The different preparations described in the present invention may be tablets, as long as the lubricated granules are compressed into tablets with a tablet extruder and then coated.

The different preparations according to the present invention may also be compound capsules, as long as the lubricated particles are filled into the capsules.

The present invention proposes for the first time a compound preparation of an anti-inflammatory and analgesic drug ibuprofen and a central analgesic drug tramadol. The analgesic effect of the compound preparation is far better than the analgesic effect of increasing any one of the single medicines. And this compound rarely shows the side effects of opioid analgesics such as addiction, tolerance, constipation, and respiratory failure. It can greatly improve the effectiveness of treating pain. Best practice

The effectiveness of this new formulation can be demonstrated by a variety of pharmacological methods. For example, one of the methods is to use the mouse acetic acid writhing method (H. Collier et al., Br. J. Pharmacol., 32, 295 (1968)) to compare ibuprofen, tramadol, and The efficacy of the compound. The results of this method are usually very close to the results of experiments on humans. In the test of the analgesic effect of tramadol, ibuprofen and the mixture of these two components, according to the above experimental method, tramadol hydrochloride was completely dissolved in distilled water, and ibuprofen was completely dissolved. Dissolved in distilled water or completely dissolved in distilled water containing 2% by volume of Tween 80 (containing 100% polysorbate 80), formulated into various doses of tramadol hydrochloride, ibuprofen, tramadol And ibuprofen mixture solution. Select female mice weighing 15-22 g. By oral route, each group of mice was injected with different doses of tramadol hydrochloride, ibuprofen, tramadol and ibuprofen mixture solutions, and another group of mice was injected with distilled water or a volume percentage of 2 in the same way. Tween 80% distilled water was used as a control group. Each group of mice was administered at 0.4ml / 10g.

30 minutes later, each group of mice was injected with a volume ratio of 0.6% acetic acid 0.2ml ₀ and the number of writhing in 15 minutes was continuously observed. When the abdominal muscle tissue of the mouse contracts with back arching and limb extension, it is considered a "twisted body" symptom.

Tramadol and ibuprofen are mixed in different proportions, and multiple doses of the compound in each group are taken (generally 4 to 6 groups of doses). Based on the above experimental design, the analgesia of each group can be measured after 30 minutes. effect. This experimental design also allows for completely random testing of the effects of various single-dose doses. When 10, 20, 30 mg / kg tramadol was used in combination with 50 or 100 mg / kg ibuprofen, the number of writhing induced by acetic acid in test mice was significantly lower than that of tramadol 30mg / kg and ibuprofen 100 mg / kg The number of twists observed when used alone.

In this experiment, the effect produced by the present invention is very obvious: Tramadol and ibuprofen show a synergistic analgesic effect, and the amount of these two components in the compound is less than Tramadol, which can produce the same analgesic effect, respectively. And ibuprofen dosage.

The mass ratio of tramadol and ibuprofen can generally be in the range of 1: 1 to 1. · 50. The compounds mixed in certain proportions show a synergistic analgesic effect. For example, according to the mixture of tramadol and ibuprofen with a mass ratio of 1: 1 to 1:20, the more accurate ratio is from 1: 2 to The ideal ratio is from 1: 2 to 1:15. The tramadol-ibuprofen complex in this quality range has been shown to work synergistically for analgesia.

The following experimental samples more accurately describe this new formulation, and these two sets of experimental samples are only intended to clarify the invention, but not to limit the invention.

The mass ratios of tramadol hydrochloride and ibuprofen in samples A and B were 1: 5.33 and 1: 4, respectively. To obtain these two dosage forms, appropriate amounts of components 1 to 4 should be placed in a high-efficiency granulator or an ordinary granulator and mixed. It is then granulated in water or other suitable liquid and dried in a dryer. Grind the dried granules and add components 5-7 to mix them. The lubricated granules were compressed into tablets of 400 mg and 300 mg with a tablet extruder, respectively. The above steps are performed according to the traditional tablet manufacturing process. The final product can be wrapped with a traditional coating. At the same time, the above formula can also be made into compound capsules. An appropriate amount of components 1 to 4 should be placed in an efficient granulator or an ordinary granulator and mixed. Water or other suitable liquid is then added to form granules and dried in a dryer. The dried granules are then mixed and added with components 5-7. The lubricated granules were filled into capsules and made into capsules with masses of 400 mg and 300 mg, respectively. The above steps are all performed according to the traditional capsule making process.

The novelty of this invention lies in a compound drug made of ibuprofen and tramadol to improve and enhance the analgesic effect.

The ideal formulation of the invention is that each dosage unit contains (1) 80mg-800mg ibuprofen or a pharmaceutically acceptable salt thereof, (2) 12.5mg-200mg tramadol or a pharmaceutically acceptable salt thereof, and (3) Pharmaceutical excipients commonly used in tablets and capsules.

Claims

A compound oral preparation of ibuprofen-tramadol according to claim, characterized in that the compound oral preparation is a compound analgesic medicine preparation containing tramadol or its pharmaceutically acceptable salts and ibuprofen or its pharmaceutically acceptable salts .

2. The ibuprofen-tramadol compound oral preparation according to claim 1, wherein the formula comprises a tramadol or a pharmaceutically acceptable salt thereof and ibuprofen or a pharmaceutically acceptable salt thereof. The mass ratio of tramadol and ibuprofen can be between 1: 1 and 1:50.

3. The ibuprofen-tramadol compound oral preparation according to claim 1, wherein the formula comprises a tramadol or a pharmaceutically acceptable salt thereof and an ibuprofen or a pharmaceutically acceptable salt thereof. Class, the ideal mass ratio range is between 1: 1 and 1:20, and the range is better between 1: 2 and 1:15.

4. The ibuprofen-tramadol compound oral preparation according to claim Cuiqiu 1, characterized in that the formula contains (1) 80mg-800mg ibuprofen or a pharmaceutically acceptable salt thereof, (2 ) 12.5mg-200mg tramadol or its pharmaceutically acceptable salts, and (3) pharmaceutically acceptable excipients commonly used in the preparation of tablets or capsules.

5. The ibuprofen-tramadol compound oral preparation according to claim 4, characterized in that the medicinal auxiliary material may be microcrystalline cellulose, pregelatinized starch, starch sodium glycolate, gum State dimorphized silicon and magnesium stearate.

6. A method for preparing an ibuprofen-tramadol compound oral preparation, characterized in that: an appropriate amount of tramadol or a pharmaceutically acceptable salt thereof and ibuprofen or a pharmaceutically acceptable salt thereof are added to necessary medicinal products The excipients are mixed in a granulator, then granulated in water or other liquids, and dried, and the dried granules are ground, and other medicinal excipients are added and mixed with them. After lubrication The granules can be made into different preparations as required.

7. The ibuprofen-tramadol compound oral preparation according to claim 6, wherein the different preparations can be tablets, as long as the lubricated granules are compressed by a tablet extruder. It can be tableted and then coated.

8. An ibuprofen-tramadol compound oral preparation according to claim 6, It is characterized in that the different preparations can also be compound capsules, as long as the lubricated particles are filled into the capsules.