CN108403651A

CN108403651A - dezocine oral preparation

Info

Publication number: CN108403651A
Application number: CN201810420839.9A
Authority: CN
Inventors: 葛光华; 刘景龙; 马晓军; 杨菡; 石晶萍; 李浩冬; 董达文
Original assignee: Yangtze River Pharmaceutical Group Co Ltd
Current assignee: Yangtze River Pharmaceutical Group Co Ltd
Priority date: 2015-02-13
Filing date: 2015-02-13
Publication date: 2018-08-17
Also published as: CN104622791A

Abstract

The invention discloses a kind of oral preparation of dezocine, the dezocine oral preparation is suitable for unit formulation comprising the auxiliary material of the dezocine of 5mg~150mg and optional pharmaceutically acceptable oral preparation.In addition, the invention also discloses the Preparation method and uses of above-mentioned oral preparation.Clinical test shows that in dosage range, dezocine oral preparation of the invention has similar blood concentration with commercially available dezocine injection, and adverse reaction is slight, and administration is more convenient.

Description

Dezocine oral preparation

The application is a divisional application with application number 201510080325.X and invention name 'dezocine oral preparation' filed on 13/2/2015

Technical Field

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a dezocine oral preparation, a preparation method of the dezocine oral preparation, and an application of the dezocine oral preparation in pain treatment.

Background

Dezocine (Dezocine), its chemical name is: 13-amino-5, 6,7,8,9,10,11, 12-octahydro-5-methyl-5, 11-methylenebenzocyclodecen-3-ol. CAS: 53648-55-8.

The structural formula is as follows:

dezocine is a powerful opioid analgesic, which has both agonist and antagonist effects, shows different characteristics by having affinity to receptor subtypes different from other opioid drugs, has stronger analgesic effect than pentazocine and smaller addiction, is mainly used for treating pains of patients suffering from moderate to severe pain and chronic pain after operation, visceral colic and late-stage cancer clinically, has the analgesic strength, the onset time, the action duration and the maximum analgesic effect equivalent to morphine and is 5-9 times stronger than dolantin, has slight side effect and good tolerance, and only markets a dezocine injection formulation at home and abroad at present.

Chinese patent CN104257615A describes a dezocine lyophilized pharmaceutical composition and its preparation method, wherein dezocine, cosolvent, excipient, stabilizer, and acid-base modifier are used to prepare a solution, and the lyophilized composition is obtained after lyophilization.

Chinese patent CN104224734A introduces a dezocine freeze-dried pharmaceutical composition and its preparation method, which comprises: dezocine, freeze-dried excipient, antioxidant, acid-base pH regulator, etc.

The above patents all only describe the preparation method of the lyophilized preparation for injection; compared with injection administration, oral administration is the most common and most convenient and economic means, the administration is convenient, no pain is caused, the stability of the medicine is high, and the dosage can be accurately calculated. However, the oral preparation is unstable in absorption, and when dezocine is administered by injection, glucuronidation occurs mainly in the liver, and excretion occurs mainly in the form of a conjugate of glucuronic acid. On the other hand, no report of oral administration adverse reactions of dezocine exists at present, adverse reactions different from injections may exist by oral administration of dezocine, and the adverse reactions need to pass through proper dosage and prescription so as to avoid adverse reactions. It is therefore very difficult to develop an oral formulation of dezocine according to the prior art.

Disclosure of Invention

The inventor finds out a dezocine oral preparation through a great deal of research, and achieves oral administration and treatment effects under a certain dosage.

The invention aims to provide an oral preparation of dezocine.

The second purpose of the invention is to provide a preparation method of the dezocine oral preparation.

The third purpose of the invention is to provide the application of the dezocine oral preparation.

Specifically, the invention provides an oral dezocine preparation, wherein each unit preparation of the oral dezocine preparation comprises 5-150 mg of dezocine and optional pharmaceutically acceptable auxiliary materials of the oral preparation. By unit formulation is meant each tablet in a tablet, each tube of oral solution, each bag of granules, or each capsule of capsules.

In a preferred embodiment of the present invention, the unit dosage form of the dezocine oral preparation provided by the present invention is orally taken three times a day, and the dezocine oral preparation comprises 5-50 mg of dezocine and optionally pharmaceutically acceptable auxiliary materials for oral preparation.

In a preferred embodiment of the present invention, the unit dosage form of the dezocine oral preparation provided by the present invention is orally taken once a day, and the dezocine oral preparation comprises 10-100 mg of dezocine and optionally pharmaceutically acceptable auxiliary materials for oral preparation.

In an embodiment of the present invention, the dezocine oral preparation provided by the present invention is selected from a pharmaceutical dosage form that can be orally administered, such as a tablet, a capsule, a granule, or an oral solution. Here, the tablets include tablets that can be orally administered, such as general tablets, sustained-release tablets, controlled-release tablets, or dispersible tablets; the capsule comprises a common capsule and various capsules such as a slow release capsule, a controlled release capsule and the like; the granules are sugar-containing or sugar-free granules.

In an embodiment of the present invention, the dezocine oral preparation provided by the present invention is preferably a tablet, more preferably a sustained release tablet.

In a preferred embodiment of the present invention, the dezocine oral preparation provided by the present invention is a dezocine tablet, wherein the pharmaceutically acceptable adjuvants of the oral preparation comprise a filler, a disintegrant, a binder and a lubricant.

In a preferred embodiment of the present invention, the dezocine oral preparation provided by the present invention is a dezocine sustained-release tablet, wherein the pharmaceutically acceptable excipients of the oral preparation comprise a filler, a sustained-release material, a binder and a lubricant.

In an embodiment of the present invention, the present invention provides an oral dezocine preparation, wherein the filler is selected from one or more of microcrystalline cellulose, lactose, starch, pregelatinized starch, mannitol, and sorbitol, and is preferably microcrystalline cellulose.

In an embodiment of the present invention, the dezocine oral preparation provided by the invention, wherein the sustained-release material is selected from one or more of hypromellose, hyprolose, methylcellulose and ethylcellulose, and hypromellose is preferred.

In an embodiment of the present invention, the present invention provides an oral dezocine preparation, wherein the disintegrant is one or more selected from sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose, and dry starch.

In an embodiment of the present invention, the present invention provides an oral formulation of dezocine, wherein the binder is one or more of hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, povidone, or crospovidone.

In an embodiment of the present invention, the dezocine oral preparation provided by the present invention, wherein the lubricant is one or more of magnesium stearate, talc, aerosil and sodium fumarate stearate.

In a second aspect, the present invention provides a method for preparing the above dezocine oral preparation, which comprises mixing 5 mg-150 mg of dezocine with optional pharmaceutically acceptable adjuvants for oral preparation, and formulating into an orally administrable dosage form.

In a third aspect, the invention provides the use of the oral formulation of dezocine as described above for the preparation of a medicament for the treatment of patients with moderate to severe pain and chronic pain after surgery.

The dezocine oral preparation provided by the invention contains a specific amount of dezocine, can effectively treat moderate to severe pain and chronic pain after operation by being taken three times a day or once a day, realizes the treatment effect and has no toxic and adverse effect. Compared with the dezocine injection used for chronic pain in the prior art, the dezocine injection is administered once every 3-6 hours when needed; the oral dezocine preparation achieves the effect of injection administration through oral administration, and is taken once a day for chronic pain.

Drawings

FIG. 1: the time curve (N-5) of single oral administration of dezocine sustained release tablets with different specifications by healthy adult subjects.

FIG. 2: healthy adult subjects compared the drug profiles of oral administration of standard or sustained release tablets of dezocine (10mg) (N ═ 5).

FIG. 3: healthy adult subjects compared the drug profiles of oral administration of standard or sustained release tablets of dezocine (15mg) (N ═ 5).

FIG. 4: healthy adult subjects compared the time curve of oral administration of standard or sustained release tablets (20mg) of dezocine (N ═ 5).

FIG. 5: healthy adult subjects compared the time curve of oral administration of standard or sustained release tablets of dezocine (25mg) (N ═ 5).

FIG. 6: healthy adult subjects compared the drug profiles of oral administration of standard or sustained release tablets of dezocine (30mg) (N ═ 5).

FIG. 7: the dosing profile of dezocine (15mg) in healthy adult subjects was varied (N15).

Detailed Description

The following specific examples are provided to assist the reader in better understanding the present invention, but the following examples are not to be construed as limiting the invention.

Example 1: preparation of dezocine oral solution

Dezocine oral solution

The preparation method comprises the following steps: weighing the crushed and sieved dezocine raw material, adding the purified water and lactic acid according to the prescription amount, dissolving, adjusting the pH value to 3.8, filtering and sterilizing.

Example 2: preparation of dezocine tablet

Prescription of dezocine tablets:

the preparation method comprises the following steps: weighing the crushed and sieved dezocine raw material, mixing the dezocine raw material with lactose, microcrystalline cellulose and carboxymethyl starch sodium according to the formula amount, adding a proper amount of 10% hydroxypropyl methylcellulose solution, uniformly mixing to prepare a proper soft material, sieving by a 16-mesh sieve, preparing into granules, drying at 60 ℃, sieving the dry granules by a 20-mesh sieve, uniformly mixing with magnesium stearate, and tabletting.

Example 3: preparation of dezocine sustained-release tablets

Prescription of dezocine sustained-release tablets:

the preparation method comprises the following steps: weighing the crushed and sieved dezocine raw material, uniformly mixing the dezocine raw material with the microcrystalline cellulose and the povidone K30 according to the formula amount, adding 5% PVP 80% ethanol solution, mixing to prepare a proper soft material, sieving with a 16-mesh sieve, granulating, drying at 60 ℃, sieving dry granules with a 18-mesh sieve, granulating, adding hydroxypropyl methylcellulose (K4M) and magnesium stearate, uniformly mixing, tabletting and coating.

Example 4 preparation of Dizocine tablets

1. Dezocine tablet

Prescription:

Example 5: preparation of dezocine sustained-release tablets

Dezocine sustained release tablet

Prescription:

Effect example 1: study of pharmacodynamics

The only injection of dezocine is on the market at home and abroad, and no report of relevant oral curative effect exists, so that the influence of the dezocine and morphine on heat radiation and hot plate pain is adopted as the basis for judging whether the dezocine is effective or not after being orally taken compared with mice and rats.

The tested drugs are: dezocine oral solution as described in example 1

Positive drugs: morphine hydrochloride injection

The administration mode comprises the following steps: respectively adopting normal saline to dilute dezocine oral solution and morphine hydrochloride injection, and performing intragastric administration. Administration volume: 10 ml/kg.

Effect of dezocine on pain caused by heat radiation of mice

The method comprises the following steps: female ICR mice were gavaged with 5, 10, 20, 40mg/kg dezocine and 40mg/kg morphine, and controls were given the same volume of saline. After 20 minutes, the pain-causing latency of the mice was measured with a photothermal pain meter.

Table 1: influence of mouse gavage on incubation period of photo-thermal pain

The data in the table are mean ± SD, n is 10. P <0.05, P <0.01, P <0.001

As a result: when the mouse is administrated with dezocine at 10, 20 and 40mg/kg by gastric lavage, the incubation period of tail pain of the mouse caused by light and heat can be obviously prolonged. ED50 was 5.9mg/kg, ED95 was 9.9 mg/kg. Under the experimental condition, 40mg/kg of morphine also has the good effect of prolonging the tail flick incubation period.

Effect of dezocine on Hot plate-induced pain in mice

The method comprises the following steps: male ICR mice, placed on a 55 ℃ hot plate, were challenged with a first lick followed by a paw withdrawal. Mice with pain threshold of 20-35 seconds were selected, and 5 hours later, dezocine (10, 40, 100mg/kg), or morphine (100mg/kg) was gavaged, and the same volume of physiological saline was administered as a control. After 20 minutes, the mixture was placed on a hot plate at 55 ℃ and the time of the first licking was counted.

Table 2: influence of gavage dezocine on hot plate-induced licking latency of mice

The data in the table are mean ± SD, # P <0.001

As a result: when the mice are gavaged with dezocine of 10, 40 and 100mg/kg, the foot licking latency period of the mice can be obviously prolonged. ED50 was 9.4mg/kg and ED95 was 23.0 mg/kg. Under the experimental condition, 100mg/kg of morphine also has good effect of prolonging the latent period.

Effect of dezocine on pain caused by heat radiation of rats

The method comprises the following steps: male wistar rats, fasted for 12 hours, were gavaged with dezocine (1.25, 2.5, 5.0, 10.0, 20.0, 40.0mg/kg), or morphine (5.0, 10.0mg/kg), and controls were given the same volume of saline. After 20 minutes, the pain-causing latency of the rats was measured using a photothermal pain meter.

Table 3: effect of rat gavage on incubation period of photo-thermal pain

The latency data in the table are mean ± SD, # p <0.01, # p <0.001

As a result: see table 3 for details. When the gavage is administered to rats at a dose of more than 2.5mg/kg, the incubation period of tail pain of the rats caused by light and heat can be obviously prolonged. ED50 was 1.5mg/kg, ED95 was 1.9 mg/kg. Rats administered with 10mg/kg morphine also had a good effect of extending the incubation period.

And (4) conclusion: the results of the experiments show that oral dezocine has ED50 values of 5.9, 9.4 and 1.5mg/kg in mouse thermoalgesic, mouse hotplate and rat thermoalgesic models, respectively. The pain relieving effect of dezocine is stronger under the same dosage.

Effect example 2: single oral dezocine common tablet tolerance study in healthy subjects

And (3) experimental design:

30 healthy adult subjects, randomized into 6 groups of 5 persons each, were given the usual tablets of dezocine described in examples 2 and 4 at 5, 10, 15, 20, 25, 30mg doses, respectively, according to body weight. The medicine is taken with warm boiled water in the morning, and is taken once.

On the low to high dose basis, 1 study group was performed daily for safety reasons, and the next study group was performed after the previous group was confirmed to be safe to take the drug. If the number of cases with 1 serious adverse event or moderate or more adverse events in the previous dose group is more than or equal to 50 percent, the test is terminated and the next dose test is not carried out.

As a result:

the main pharmacokinetic parameters of healthy adult subjects taking different doses of standard tablets of dezocine are shown in table 1. Subject orally takes 5-30mg dezocine, dezocine is absorbed very quickly, T_max1.0-1.2h, and is relatively slow to eliminate in vivo_1/2Is 3.7-4.1 h. With increasing dosage, C_maxIn a linear increase, see fig. 1. In the range of 5-30mg, the subjects are safe and tolerant, and adverse events in the test process are mild and moderate. Adverse events occur with increasing doses, with a corresponding increase in frequency and extent. The main adverse events were: nausea, vomiting, dizziness, sweating, etc.

Table 4: major pharmacokinetic parameters of normal tablets of dezocine administered orally at different doses to healthy adult subjects (N ═ 5)

Effect example 3: a single time for healthy subjects: tolerance study of oral dezocine sustained-release tablets

And (3) experimental design:

25 healthy adult subjects, randomly divided into 5 groups by weight, 5 persons in each group, were administered with the dezocine sustained-release tablets of examples 3 and 5 of the present application at doses of 10, 15, 20, 25mg, and 30mg, respectively, once in the morning with warm and empty water.

As a result:

the main pharmacokinetic parameters of healthy adult subjects orally taking different dosages of dezocine sustained release tablets are shown in table 2. When the subject takes 10-30mg dezocine sustained release tablets orally, the absorption is obviously slowed compared with the common tablets, and T_max2.6-2.8h, the elimination in vivo is also remarkably slowed, t_1/2Is 5.7-5.9 h. With increasing dosage, C_maxThe increase is linear. In the range of 10-30mg, the subjects are safe and tolerant, and adverse events in the test process are mild and moderate. Adverse events occur with increasing frequency and extent of dosing. The main adverse events were: nausea, vomiting, dizziness, sweating, etc.

Compared with the common tablet with the same dosage, the dezocine sustained release tablet t_1/2And T_maxSignificant elongation, C_maxAlthough slightly reduced, the change was not so great as to exhibit a significant sustained-release property, as shown in FIGS. 2 to 6.

Table 5: major pharmacokinetic parameters of healthy adult subjects orally taking different dosages of dezocine sustained release tablets (N ═ 5)

Effect example 4: comparison of pharmacokinetics of dezocine (15mg) in different modes of administration in healthy subjects

And (3) experimental design:

15 adult healthy subjects, randomized into 3 groups, were designed using a 3-preparation 3-cycle double 3 × 3 latin square trial. One group is taken by injection of 15mg of dezocine, oral common tablets (15mg) and oral sustained-release tablets (15mg) in sequence; the two groups are taken according to the sequence of oral sustained-release tablets (15mg), injection dezocine 15mg and oral ordinary tablets (15 mg); the three groups are taken in the order of oral common tablet (15mg), oral sustained release tablet (15mg) and injection dezocine 15 mg; the washing period is one week.

Results

The main pharmacokinetic parameters of dezocine (15mg) in different modes of administration in healthy adult subjects are given in table 3. Oral 15mg dezocine common tablet and sustained release tablet C_max15.8 +/-3.2 and 13.9 +/-2.9 ng/ml respectively; oral 15mg dezocine common tablet and sustained release tablet_max1.1 +/-0.3 and 2.7 +/-0.7 hours respectively; injection of 15mg dezocine and oral administration of 15mg dezocine ordinary tablet or sustained release tablet_1/2Respectively for 2.7 +/-0.8, 3.8 +/-1.4 and 5.7 +/-2.1 hours; AUC of 15mg dezocine injection and 15mg dezocine oral common tablet or sustained release tablet_0-16hRespectively 85.6 + -9.4, 54.1 + -6.1 and 54.1 + -6.1 ug h/L, and the absolute bioavailability of the conventional dezocine tablet and the sustained-release tablet is 63.20% and 65.40%, respectively, as shown in FIG. 7. Adverse events: adverse events occurring with injection administration were nausea (2/15), vomiting (1/15), dizziness (1/15); the adverse events that occur with oral ordinary tablets are dizziness (1/15); the oral sustained-release tablet has no adverse event. Compared with injection administration, the oral dezocine does not produce gastrointestinal adverse reactions, and other adverse reactions are less than those of the injection.

Table 6: major pharmacokinetic parameters of different modes of administration of dezocine (15mg) in healthy adult subjects (N ═ 15)

Claims

1. The unit preparation of the dezocine oral preparation comprises 1 mg-150 mg of dezocine and optional auxiliary materials of pharmaceutically acceptable oral preparations; preferably, the unit dosage form of the dezocine oral preparation contains 5-100 mg of dezocine, and more preferably, the unit dosage form of the dezocine oral preparation contains 5-50 mg of dezocine.

2. The dezocine oral preparation of claim 1, in the form of tablets, capsules, granules, or oral solutions, preferably plain tablets or extended release tablets.

3. The dezocine oral preparation of claim 2, wherein the dezocine oral preparation is a dezocine tablet, taken three times daily.

4. The dezocine oral preparation of claim 2, wherein the dezocine oral preparation is a delayed-release tablet of dezocine, and is orally administered once a day.

5. The dezocine oral preparation of claim 2, wherein the dezocine oral preparation is a conventional dezocine tablet, and the pharmaceutically acceptable auxiliary materials for oral preparation comprise a filler, a disintegrant, a binder and a lubricant;

preferably, the filler is selected from one or more of microcrystalline cellulose, lactose, starch, pre-crosslinked starch, mannitol and sorbitol, and is more preferably microcrystalline cellulose;

the disintegrating agent is selected from one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose and dry starch;

one or more of hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, povidone or cross-linked povidone serving as the adhesive;

the lubricant is one or more of magnesium stearate, talcum powder, superfine silica gel powder and fumaric acid sodium stearate.

6. The dezocine oral preparation of claim 2, wherein the dezocine oral preparation is a dezocine sustained release tablet, wherein the pharmaceutically acceptable auxiliary materials for oral preparation comprise a filler, a sustained release material, a binder and a lubricant;

the lubricant is one or more of magnesium stearate, talcum powder, superfine silica gel powder and sodium fumarate stearate;

the slow release material is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose and ethyl cellulose, and more preferably the hydroxypropyl methylcellulose.

7. The dezocine oral preparation of claim 5, wherein the dezocine oral preparation is a common dezocine tablet, and comprises the following components in percentage by weight:

or,

8. the dezocine oral preparation of claim 6, wherein the dezocine oral preparation is a dezocine sustained release tablet, and comprises the following components in percentage by weight:

or,

9. use of an oral formulation of dezocine as claimed in any of claims 1 to 8 for the preparation of a medicament for the treatment of pain.