Background technology
Muscle relaxant is the medicine that can reduce skeletal muscle (striped muscle) tensity.Mainly be divided into neuromuscular blocking drug and central skeletal muscle relaxant, the former mainly acts on nerve synapse, usually as the anesthesia adjuvant, all belongs to this type of medicine as chlorine letter curare alkaloid, benzenesulfonic acid atracurium, pipecuronium bromide etc.; And the latter mainly acts on central nervous system's (beyond synapse), is generally used for the pain alleviating the skeletal muscle spasm and cause, example hydrochloric acid eperisone granule, and chlorzoxazone, methocarbamol etc. all belongs to this type of medicine.Wherein methocarbamol is just clinical at home and abroad the being extensive use of eighties.Be applicable to that clinically treating various acute and chronic soft tissues (muscle, ligament, fascia) sprains, dampens, motion back muscular soreness, the old pain that causes of decreasing of muscle, neuralgia, arthralgia, rheumatalgia, the fibrous connective tissue inflammation, spondylitis is by the muscle spasm that central neuropathy causes, chronic fascitis etc.
The acute and chronic soft tissue that a variety of causes causes (muscle, ligament, fascia) knob is hindered, is dampened, motion back muscular soreness, the caused pain of muscular strain, the muscle spasm that is caused by central neuropathy, chronic fascitis etc. and the light moderate pain that is caused by a variety of causes such as neuralgia, lumbago, shoulder pain, myalgia, arthralgia, traumatic injury pain etc. are frequently-occurring disease and commonly encountered diseases general, the most common in the daily life, bring many miseries and worry to people, have a strong impact on people's work, study and rest.It has seriously hindered people's work, the second largest commonly encountered diseases that becomes disability after 50 years old because of, be only second to the heart disease sickness rate.According to western countries statistics, osteoarthritis has accounted for 2.3% of clinic case at present, is just threatening people's health, and there are confidential relation at the generation and the age of osteoarthritis, and it is 2%-3% that the age is lower than 45 years old sickness rate; 45-64 year be 24.5%-30%, surpass 65 years old can be up to 58%-68%, and women's sickness rate is higher than the male.
For as above disease, domestic analgesic, the anti-inflammatory analgesic treatment of using more, compare with above-mentioned medicine as the chlorzoxazone of aspirin, acetaminophen, diclofenac sodium and listing in recent years and compound chlorzoxazone etc., the methocarbamol dry suspension has anti-inflammatory analgesic, the skeletal muscle relaxation effect is strong, and the low characteristics of toxic and side effects.The methocarbamol dry suspension of developing, expectation can produce good economic benefit and social benefit.
Methocarbamol (Robaxin
/ Robaxin
-750) be the lax medicine of central skeletal muscle of SCHWARZ PHARMA company exploitation, get permission listing at FDA January nineteen eighty-two.USP23 has recorded the tablet of methocarbamol raw material, injection and 500mg thereof and 750mg.Sell for many years in American-European countries such as the U.S., Canada, occupy certain market share always.Methocarbamol can make skeleton lax, but consciousness is disappeared, and this product has anticonvulsant action, can resist faint from fear due to strychnine and the electricity irritation, its mechanism is for suppressing the multisynaptic reflex of spinal cord.In addition still can calmness, analgesia, antiinflammatory.Clinical being extensive use of of methocarbamol reported the new purposes of methocarbamol when clinical heavy dose is used again in succession in recent years, and its curative effect is safe and reliable.
The methocarbamol dosage form mainly contains injection and oral formulations (mainly being tablet and capsule) at present, has instability, absorbs few, the defective of mouthfeel difference, the dry suspension type that the present invention makes methocarbamol, the rapid disintegrating medicinal stripping of dry suspension chance water is fast, the bioavailability height.Patient Geng Yi with respect to old man and dysphagia takes simultaneously, and mouthfeel is better, taking convenience, and the patient is easy to accept, and is easy to carry.Be insoluble in water thereby overcome methocarbamol, the defective that bioavailability is supported,
Summary of the invention
The invention provides methocarbamol dry suspension type, said preparation can be a powder type, can be particle form also, contains the active component methocarbamol of effective dose and the medicine acceptable carrier of suitable preparation dry suspension type.
The medicine acceptable carrier of described suitable preparation dry suspension type comprises cellulose derivative, correctives, binding agent, cellulose derivative hydroxypropyl methylcellulose preferably wherein, microcrystalline Cellulose, correctives is sucrose preferably, and binding agent is the mixture of second alcohol and water preferably.
Prescription of the present invention is composed as follows:
Methocarbamol 250-1000g
Hydroxypropyl methylcellulose (E
5-LV) 50-200g
Microcrystalline Cellulose 100-400g
Sucrose 100-400g
50% ethanol water 10-50ml
Make 1000 bags
Preferably
Methocarbamol 500g
Hydroxypropyl methylcellulose (E
5-LV) 100g
Microcrystalline Cellulose 200g
Sucrose 200g
50% ethanol water 20ml
Make 1000 bags
To preferred prescription of the present invention, preparation method is as follows:
With the methocarbamol crushing screening, hydroxypropyl methylcellulose E
5-LV, microcrystalline Cellulose, sucrose crushing screening; Weighing with mix;
Take by weighing above-mentioned supplementary material respectively according to recipe quantity; Above-mentioned supplementary material is inserted mix homogeneously in the mixer; Granulate:, granulate with 20 order nylon wires with 50% ethanol system soft material; Drying, granulate, packing.
The present invention preferably writes out a prescription and obtains through screening, and screening process is as follows:
The screening of prescription:
In the prescription screening process, the sedimentation suspendible adopts hydroxypropyl methylcellulose E than us in order to reach preferably
5-LV, sodium carboxymethyl cellulose, methylcellulose are as suspending agent, and filler uses microcrystalline Cellulose, below is the screening of several suspending agents:
Prescription 1
Methocarbamol 500g
Microcrystalline Cellulose 200g
Hydroxypropyl methylcellulose (E
5-LV) 100g
Sucrose 200g
50% ethanol is an amount of
Make 1000 bags
Prescription 2
Methocarbamol 500g
Microcrystalline Cellulose 200g
Sodium carboxymethyl cellulose 100g
Sucrose 200g
50% ethanol is an amount of
Make 1000 bags
Prescription 3
Methocarbamol 500g
Microcrystalline Cellulose 200g
Methylcellulose 100g
Sucrose 200g
50% ethanol is an amount of
Make 1000 bags
With reference to the assay method of settling volume ratio in two middle appendix I0 suspensoids of CPS2000 version, get this product 1g and place the firmly jolting 1 minute of 50ml tool plug graduated cylinder, write down the beginning height H of suspended matter
0, left standstill 3 hours, write down the final height H of suspended matter
1, calculate the settling volume ratio and should be not less than 0.90, the results are shown in Table 1
Table 1 settling volume compares measurement result
The prescription number | Prescription 1 | Prescription 2 | Prescription 3 |
The settling volume ratio | 0.96 | 0.91 | 0.88 |
Shown by above result of the test: prescription 1 settling volume is than best, still be chosen in the screening of carrying out mouthfeel on the basis of prescription 1, as follows:
Prescription 4
Methocarbamol 500g
Microcrystalline Cellulose 300g
Hydroxypropyl methylcellulose E
5-LV100g
Sucrose 100g
50% ethanol is an amount of
Make 1000 bags
To carry out settling volume than checking be 0.91 to writing out a prescription 4, write out a prescription 1 and write out a prescription 4 mouthfeel relatively again, method is as follows: the user gargles 3 times with boiled water after meal half an hour, get one bag of dried suspendible and wash the back clothes open down with warm water, think satisfied person 5 minutes, think and think and think to be difficult to the receiver 0 minute in gastrointestinal disease patient 1 minute in general person 3 minutes.The result is as follows:
The The selection result of table 2 mouthfeel
Sequence number | Sex | Age | Prescription 1 | Prescription 4 |
1 | The man | 27 | 5 | 1 |
2 | The woman | 50 | 3 | 3 |
3 | The man | 32 | 5 | 3 |
4 | The man | 61 | 1 | 1 |
5 | The woman | 21 | 5 | 1 |
6 | The man | 18 | 5 | 3 |
7 | The man | 20 | 5 | 3 |
8 | The woman | 12 | 3 | 1 |
9 | The woman | 15 | 3 | 3 |
10 | The woman | 45 | 3 | 3 |
11 | The man | 63 | 5 | 3 |
12 | The woman | 50 | 5 | 1 |
13 | The man | 29 | 5 | 1 |
14 | The woman | 26 | 3 | 1 |
15 | The woman | 24 | 3 | 3 |
16 | The man | 32 | 5 | 3 |
17 | The woman | 47 | 5 | 3 |
18 | The woman | 30 | 5 | 1 |
19 | The man | 29 | 5 | 5 |
20 | The woman | 31 | 3 | 3 |
21 | The woman | 37 | 5 | 3 |
22 | The man | 25 | 5 | 3 |
23 | The woman | 33 | 5 | 1 |
24 | The man | 62 | 3 | 3 |
25 | The man | 57 | 3 | 1 |
26 | The man | 34 | 5 | 3 |
27 | The woman | 25 | 5 | 3 |
28 | The man | 19 | 5 | 1 |
29 | The man | 33 | 3 | 3 |
30 | The woman | 39 | 5 | 3 |
31 | The man | 28 | 3 | 3 |
32 | The woman | 21 | 3 | 1 |
33 | The man | 48 | 5 | 3 |
34 | The woman | 61 | 5 | 1 |
35 | The man | 37 | 5 | 5 |
36 | The woman | 27 | 3 | 3 |
37 | The man | 22 | 5 | 3 |
38 | The man | 18 | 5 | 1 |
39 | The woman | 15 | 5 | 1 |
40 | The man | 50 | 3 | 1 |
41 | The woman | 58 | 5 | 3 |
42 | The woman | 30 | 5 | 1 |
43 | The man | 39 | 5 | 3 |
44 | The woman | 23 | 5 | 3 |
45 | The woman | 28 | 5 | 3 |
46 | The man | 16 | 5 | 3 |
47 | The woman | 17 | 3 | 1 |
48 | The man | 18 | 5 | 1 |
49 | The man | 35 | 5 | 3 |
50 | The man | 34 | 5 | 3 |
Average mark | / | / | 4.32 | 2.40 |
Above result shows: the mouthfeel of prescription 1 is better.
Three stability influence factorial experimentss:
(1) strong illumination test:
Get 030910 batch of dried suspendible of methocarbamol and place glass dish, placed 10 days under the illumination of 4500LX ± 500LX, detect in sampling in 0,5,10 day, testing result sees Table 3:
Table 3 strong illumination result of the test
Blanking time (my god) | Outward appearance, color and luster | The settling volume ratio | Related substance | Content (%) |
Guaifenesin (%) | Other impurity levels (%) |
0 5 10 | White particle and powder white particle and powder white particle and powder | 0.95 0.95 0.93 | 0.24 0.22 0.24 | 0.07 0.08 0.08 | 99.8 99.9 99.1 |
(2) hot test:
Get 030910 batch of dried suspendible of methocarbamol and place glass dish, placed 10 days in 60 ℃ calorstat, detect in sampling in 0,5,10 day, testing result sees Table 4:
60 ℃ of thimble test results of table 4
Blanking time (my god) | Outward appearance, color and luster | The settling volume ratio | Related substance | Content (%) |
Guaifenesin (%) | Other impurity levels (%) |
0 5 10 | White particle and powder white particle and powder white particle and powder | 0.95 0.94 0.95 | 0.24 0.23 0.24 | 0.07 0.08 0.11 | 99.8 99.0 99.5 |
(3) high humidity result of the test:
The dried suspendible of methocarbamol of getting 030910 batch places glass dish, respectively at relative humidity 75% (NaCl saturated solution), 92.5% (KNO
3Saturated solution) placed in the calorstat 10 days, and detected in sampling in 0,5,10 day, testing result sees Table 5 and table 6:
Table 5 75% high humidity stability test
Blanking time (my god) | Outward appearance, color and luster | Hygroscopicity (%) | The settling volume ratio | Related substance | Content (%) |
Guaifenesin (%) | Other impurity levels (%) |
0 5 10 | White particle and powder white particle and powder white particle and powder | 2.55 2.97 | 0.95 0.93 0.91 | 0.24 0.23 0.25 | 0.07 0.10 0.09 | 99.8 99.0 100.1 |
Table 6 92.5% high humidity stability test result
Blanking time (my god) | Outward appearance, color and luster | Moisture absorption (%) | The settling volume ratio | Related substance | Content (%) |
Guaifenesin (%) | Other impurity levels (%) |
0 5 10 | White particle and powder white particle and powder white particle and powder | 16.31 18.92 | 0.95 0.92 0.91 | 0.24 0.25 0.26 | 0.07 0.10 0.10 | 99.8 99.2 99.4 |
Above result of the test shows, this product is all stable under the condition of illumination, 60 ℃ of high temperature and high humidity.
The testing data of stability study
We have carried out the test that keeps sample of constant temperature accelerated test, room temperature to the methocarbamol dry suspension of trial-production, thereby its stability has been carried out preliminary investigation, press the assay method of clinical quality standard (draft) regulation, sample appearance character, settling ratio, related substance, content project are detected.
The source of sample is the Tianjin Hankang Medicine Bioisystech Co., Ltd, and lot number is respectively 030910,2909 bag, 030912,2903 bag, 030914,2928 bag.Remove outer package as requested.
One, constant temperature accelerated stability test:
Get the methocarbamol dry suspension, lot number 030910,030912,030914, packed with aluminum-plastic composite membrane, constant temperature is placed under 40 ℃ ± 2 ℃ relative humiditys 75% (NaCL saturated solution) condition, and respectively at 0,1,2,3, the sampling in June detects, testing result sees Table 7
Two, the room temperature study on the stability that keeps sample:
Get the methocarbamol dry suspension, lot number 030910,030912,030914, packed with aluminum-plastic composite membrane, under the natural conditions in the breadboard sample cabinet, place, respectively at 0,3, the sampling in June detects, testing result sees Table 8
Three, conclusion:
1 constant temperature accelerated test:
The result shows: this product is under the condition of 40 ℃ ± 2 ℃ of relative humiditys 75%, and in 6 months of having investigated, each investigates every index of project does not have significant change, has stability preferably.
The investigation that keeps sample of 2 room temperatures:
Keep sample in room temperature and to investigate test and show: this product was placed 6 months at room temperature condition, had stability preferably, and this work is still underway.
Through the preliminarily stabilised evidence: the methocarbamol dry suspension keeps sample through constant temperature accelerated test and room temperature and investigates test and think that this product is stable, and keeping life can be fixed tentatively 2 years.
The present invention shows preparation of the present invention and prescription in stability through comparative study, bioavailability, and infiltration rate, mouthfeel, preparation method, aspects such as industrialization all are better than prior art, have obtained beyond thought technique effect.
The specific embodiment
The present invention is described further by the following examples, but not as limitation of the present invention.
Embodiment 1
Methocarbamol 500g
Hydroxypropyl methylcellulose (E
5-LV) 100g
Microcrystalline Cellulose 200g
Sucrose 200g
50% ethanol water 20ml
Make 1000 bags
1. the preparation of supplementary material and processing:
Methocarbamol was pulverized 100 mesh sieves, hydroxypropyl methylcellulose E
5-LV, microcrystalline Cellulose, sucrose were pulverized 100 mesh sieves.
2 weighings with mix:
2-1 takes by weighing above-mentioned supplementary material according to recipe quantity respectively through the double calculating inventory of checking.
2-2 inserts mix homogeneously in the mixer with above-mentioned supplementary material.
3 granulate:
3-1 system soft material is granulated with 20 order nylon wires with 50% ethanol system soft material, and the granule that makes should not have fine powder, does not neatly have rectangular.
3-2 drying: 50+2 ℃ temperature, in drying baker inner drying 6-7 hour.
The 3-3 granulate: in pelletization, excessive granule is arranged, the granulate that need sieve just can meet the granularity regulation under the granule item; The employing oscillating granulator that sieves is selected 18 mesh sieve granulate for use, crosses 40 mesh sieves then, makes granule not have fine powder.
4. mensuration granule content.
5 inspections of semifinished product: dry suspension need check that outward appearance, settling volume when pack after the assay was approved by the quality standard requirement.
6 pack according to the requirement of product, and packing back warehouse-in can dispatch from the factory after the assay was approved according to quality standard.
Embodiment 2
Methocarbamol 250g
Hydroxypropyl methylcellulose (E
5-LV) 50g
Microcrystalline Cellulose 100g
Sucrose 100g
50% ethanol water 10ml
Make 1000 bags
2. the preparation of supplementary material and processing:
Methocarbamol was pulverized 100 mesh sieves, hydroxypropyl methylcellulose E
5-LV, microcrystalline Cellulose, sucrose were pulverized 100 mesh sieves.
2 weighings with mix:
2-1 takes by weighing above-mentioned supplementary material according to recipe quantity respectively through the double calculating inventory of checking.
2-2 inserts mix homogeneously in the mixer with above-mentioned supplementary material.
3 granulate:
3-1 system soft material is granulated with 20 order nylon wires with 50% ethanol system soft material, and the granule that makes should not have fine powder, does not neatly have rectangular.
3-2 drying: 50 ± 2 ℃ temperature, in drying baker inner drying 6-7 hour.
The 3-3 granulate: in pelletization, excessive granule is arranged, the granulate that need sieve just can meet the granularity regulation under the granule item; The employing oscillating granulator that sieves is selected 18 mesh sieve granulate for use, crosses 40 mesh sieves then, makes granule not have fine powder.
4. mensuration granule content.
5 inspections of semifinished product: dry suspension need check that outward appearance, settling volume when pack after the assay was approved by the quality standard requirement.
6 pack according to the requirement of product, and packing back warehouse-in can dispatch from the factory after the assay was approved according to quality standard.
Embodiment 3
Methocarbamol 1000g
Hydroxypropyl methylcellulose (E
5-LV) 200g
Microcrystalline Cellulose 400g
Sucrose 400g
50% ethanol water 50ml
Make 1000 bags
The preparation of supplementary material and processing:
Methocarbamol was pulverized 100 mesh sieves, hydroxypropyl methylcellulose E
5-LV, microcrystalline Cellulose, sucrose were pulverized 100 mesh sieves.
2 weighings with mix:
2-1 takes by weighing above-mentioned supplementary material according to recipe quantity respectively through the double calculating inventory of checking.
2-2 inserts mix homogeneously in the mixer with above-mentioned supplementary material.
3 granulate:
3-1 system soft material is granulated with 20 order nylon wires with 50% ethanol system soft material, and the granule that makes should not have fine powder, does not neatly have rectangular.
3-2 drying: 50 ± 2 ℃ temperature, in drying baker inner drying 6-7 hour.
The 3-3 granulate: in pelletization, excessive granule is arranged, the granulate that need sieve just can meet the granularity regulation under the granule item; The employing oscillating granulator that sieves is selected 18 mesh sieve granulate for use, crosses 40 mesh sieves then, makes granule not have fine powder.
4. mensuration granule content.
5 inspections of semifinished product: dry suspension need check that outward appearance, settling volume when pack after the assay was approved by the quality standard requirement.
6 pack according to the requirement of product, and packing back warehouse-in can dispatch from the factory after the assay was approved according to quality standard.
Table 7 constant temperature accelerated stability test result
The project lot number | Blanking time (moon) | Appearance luster | Settling ratio (H/H
0)
| Related substance (%) | Content (%) |
Guaifenesin | Other impurity levels |
030910 | 0 1 2 3 6 | White particle and powder white particle and powder white particle and powder white particle and powder white particle and powder | 0.95 0.94 0.93 0.95 0.94 | 0.24 0.25 0.26 0.22 0.25 | 0.07 0.11 0.12 0.09 0.16 | 99.8 100.4 99.9 99.3 99.5 |
030912 | 0 1 2 3 6 | White particle and powder white particle and powder white particle and powder white particle and powder white particle and powder | 0.94 0.95 0.96 0.94 0.93 | 0.22 0.24 0.29 0.24 0.27 | 0.10 0.09 0.11 0.12 0.18 | 100.1 100.6 99.4 99.6 99.9 |
030914 | 0 1 2 3 6 | White particle and powder white particle and powder white particle and powder white particle and powder white particle and powder | 0.94 0.93 0.95 0.94 0.95 | 0.23 0.22 0.25 0.24 0.24 | 0.09 0.08 0.10 0.11 0.15 | 100.4 99.8 100.1 99.2 99.8 |
The table 8 room temperature stability test result that keeps sample
The project lot number | Blanking time (moon) | Appearance luster | Settling ratio (H/H
0)
| Related substance (%) | Content (%) |
Guaifenesin | Other impurity levels |
030910 | 0 3 6 | White particle and powder white particle and powder white particle and powder | 0.95 0.96 0.93 | 0.24 0.22 0.27 | 0.07 0.08 0.14 | 99.8 100.0 99.2 |
030912 | 0 3 6 | White particle and powder white particle and powder white particle and powder | 0.94 0.95 0.93 | 0.22 0.22 0.26 | 0.10 0.08 0.13 | 100.1 99.8 99.5 |
030914 | 0 3 6 | White particle and powder white particle and powder white particle and powder | 0.94 0.94 0.95 | 0.23 0.23 0.25 | 0.09 0.11 0.15 | 100.4 99.6 99.8 |