CN101422438A - Composite diisopropyiarmini dichloroacetas freeze-dry preparation without adjuvant and preparation technique thereof - Google Patents

Abstract

The invention relates to a diisopropylamine dichloroacetate lyophilized preparation without accessories, and a preparation method; the preparation only contains diisopropylamine dichloroacetate and sodium gluconate, and contains no additives. The lyophilized preparation of one dosage contains 2mg to 200mg of the diisopropylamine dichloroacetate and 1.9mg to 190mg of the sodium gluconat. The proportion between the medicament and water in the preparation technique is 1 : 1 to 100; a medicine liquid is prepared first; and then a pre-freezing lyophilization technique is adopted for one or a plurality of times to carry out the preparation. The invention leads the quality of the preparation to be more easily controlled, reduces the production cost and leads the medicament use safety of a patient to be ensured more. The invention can obtain excellent effects in curing clinic liver diseases.

Description

A kind of compound diisopropylamine dichloroacetate lyophilized formulations and preparation technology who does not contain adjuvant

Technical field

The present invention relates to field of medicaments, relate in particular to a kind of compound diisopropylamine dichloroacetate lyophilized formulations and preparation technology who does not contain adjuvant.

Background technology

Compound diisopropylamine dichloroacetate is the compound preparation that diisopropylamine dichloroacetate and gluconic acid sodium salt are formed, be a kind of medicine for the treatment of hepatopathy, have and promote the liver steatolysis, reduce the liver protection function such as synthetic that liver tg is assembled, suppressed to intrahepatic fat.Life-time service confirms both at home and abroad: this medicine can obviously improve acute and chronic hepatitis, also can be used for fatty liver and other all liver malfunctions.Present domestic compound diisopropylamine dichloroacetate for injection is an aqueous injection, because compound diisopropylamine dichloroacetate case of thermal instability, under solution state, compound diisopropylamine dichloroacetate facile hydrolysis behind the high temperature sterilize and occur that content descends and phenomenons such as related substance rising, liquid drugs injection also inconvenience in storage and transportation simultaneously.

Lyophilized formulations generally adopts Freeze Drying Technique to prepare, and need to be about to exsiccant drug solution be frozen into solid in advance, under the low-temp low-pressure condition, water is directly distilled from solid state without liquid state remove then.But, in the prescription of medicine, add adjuvant (also can be called carrier or proppant) usually, as add an amount of mannitol, lactose, dextran, glucose, sodium chloride, phosphate etc. for the quality of assurance preparation and the feasibility of technology.Add adjuvant in the lyophilized formulations, though help the molding of preparation and the feasibility of technology, obviously there is deficiency in the adding of adjuvant: (1) has increased the production cost of preparation; (2) increase of prescription complexity has improved the difficulty of drug quality control; (3) a large amount of exogenous materials is introduced in the body during patient's intravenous injection medication, the probability that patient body is worked the mischief increases.

Summary of the invention

But the object of the present invention is to provide a kind of lyophilized formulations and preparation technology who does not contain the compound diisopropylamine dichloroacetate injection of any adjuvant; Can avoid the adding of adjuvant fully by the present invention, make the quality of the pharmaceutical preparations more easy to control, reduce production costs, patient's drug safety is more guaranteed.

Because the character of diisopropylamine dichloroacetate and gluconic acid sodium salt itself has determined to adopt common Freeze Drying Technique it can not be prepared into the lyophilized formulations that does not contain adjuvant.The technology of the present invention key is to adopt special repeatedly pre-freeze sublimed method freeze drying technology technology to realize the purpose of inventing, the present technique key can be improved lyophilizing sample crystallization behavior state and aeration significantly, steam is overflowed smoothly, make sublimation process carry out smoothly.Concrete freeze-dry process process is:

A.1, be cooled to-15 ~-70 ℃, per minute falls 1 ~ 2 ℃, is incubated 2 ~ 5 hours, makes sample be warming up to-10 ~-30 ℃ again, per hour heat up 2 ~ 5 ℃, keeping about 1 hour under this temperature, and then be cooled to-15 ~-70 ℃, per minute falls 1 ~ 2 ℃, is incubated 2 ~ 5 hours, so repeats pre-freeze 0 ~ 3 time;

B. again evacuation to make vacuum be 0.01 ~ 200Pa, make sample be warming up to-10 ~-30 ℃, per hour heat up 2 ~ 5 ℃, and under this temperature, carried out primary drying 2-50 hour;

C. and then make sample be warming up to 10 ~ 30 ℃, and under this temperature, be retained to vacuum and change when little, be incubated 1 hour and finish whole freeze-drying process.

Advantage of the present invention is: but a kind of lyophilized formulations and preparation technology who does not contain the compound diisopropylamine dichloroacetate injection of any adjuvant is provided; Can avoid the adding of adjuvant fully by the present invention, make the quality of the pharmaceutical preparations more easy to control, reduce production costs, patient's drug safety is more guaranteed.

Specific embodiment

Below in conjunction with embodiment the present invention is described in further details, but the present invention is not limited to these embodiment.

Embodiment 1

Prescription: (1000 bottles, dosage is for containing diisopropylamine dichloroacetate 20mg and gluconic acid sodium salt 19mg)

Diisopropylamine dichloroacetate 20g

Gluconic acid sodium salt 19g

Water for injection 1000ml

Preparation technology:

1. under cleaning condition, get freshly prepd water for injection (80% amount of writing out a prescription approximately), cool the temperature to below 40 ℃, add the diisopropylamine dichloroacetate and the gluconic acid sodium salt of recipe quantity, stir and make dissolving;

2. press the needle-use activated carbon of amount of preparation adding 0.1%, stirring and adsorbing 15 minutes, filtering decarbonization;

3. add water for injection below 40 ℃ to recipe quantity, stir evenly, with 0.22 μ m filtering with microporous membrane degerming;

4. press every bottle of fill of 1ml/ in cillin bottle, place freeze dryer, carry out lyophilization by following freeze-dry process:

A. be cooled to-40 ℃ with 1 ℃ of per minute, be incubated 2 hours, make sample be warming up to-20 ℃ again per hour to heat up 2 ℃, keeping about 1 hour under this temperature, and then be cooled to-40 ℃, be incubated 2 hours with 1 ℃ of per minute; So repeat pre-freeze 1 time;

B. again evacuation to make vacuum be 10Pa, per hour heating up 2 ℃ makes sample be warming up to-20 ℃, and carries out primary drying 20 hours under this temperature;

C. and then make sample be warming up to 10 ℃, and under this temperature, be retained to vacuum and change when little, be incubated 1 hour and finish whole freeze-drying process.

Embodiment 2 prescriptions: (1000 bottles, dosage is for containing diisopropylamine dichloroacetate 40mg and gluconic acid sodium salt 38mg)

Diisopropylamine dichloroacetate 40g

Gluconic acid sodium salt 38g

Water for injection 2000ml

Preparation technology:

1. under cleaning condition, get freshly prepd water for injection (80% amount of writing out a prescription approximately), cool the temperature to below 40 ℃, add the diisopropylamine dichloroacetate and the gluconic acid sodium salt of recipe quantity, stir and make dissolving;

2. press the needle-use activated carbon of amount of preparation adding 0.1%, stirring and adsorbing 15 minutes, filtering decarbonization;

3. add water for injection below 40 ℃ to recipe quantity, stir evenly, with 0.22 μ m filtering with microporous membrane degerming;

4. press every bottle of fill of 2ml/ in cillin bottle, place freeze dryer, carry out lyophilization by following freeze-dry process:

A. be cooled to-50 ℃ with 2 ℃ of per minutes, be incubated 3 hours, make sample be warming up to-20 ℃ again per hour to heat up 2 ℃, keeping about 1 hour under this temperature, and then be cooled to-50 ℃, be incubated 3 hours with 2 ℃ of per minutes; So repeat pre-freeze 2 times;

B. again evacuation to make vacuum be 10Pa, per hour heating up 2 ℃ makes sample be warming up to-20 ℃, and carries out primary drying 30 hours under this temperature;

C. and then make sample be warming up to 20 ℃, and under this temperature, be retained to vacuum and change when little, be incubated 1 hour and finish whole freeze-drying process.

Embodiment 3

Prescription: (1000 bottles, dosage is for containing diisopropylamine dichloroacetate 10mg and gluconic acid sodium salt 9.5mg)

Diisopropylamine dichloroacetate 10g

Gluconic acid sodium salt 9.5g

Water for injection 1000ml

Preparation technology:

1. under cleaning condition, get freshly prepd water for injection (80% amount of writing out a prescription approximately), cool the temperature to below 40 ℃, add the diisopropylamine dichloroacetate and the gluconic acid sodium salt of recipe quantity, stir and make dissolving;

2. press the needle-use activated carbon of amount of preparation adding 0.05%, stirring and adsorbing 30 minutes, filtering decarbonization;

3. add water for injection below 40 ℃ to recipe quantity, stir evenly, with 0.22 μ m filtering with microporous membrane degerming;

4. press every bottle of fill of 1ml/ in cillin bottle, place freeze dryer, carry out lyophilization by following freeze-dry process:

A. be cooled to-30 ℃ with 1 ℃ of per minute, be incubated 3 hours, make sample be warming up to-15 ℃ again per hour to heat up 2 ℃, keeping about 1 hour under this temperature, and then be cooled to-30 ℃, be incubated 3 hours with 1 ℃ of per minute;

B. again evacuation to make vacuum be 10Pa, per hour heating up 2 ℃ makes sample be warming up to-15 ℃, and carries out primary drying 15 hours under this temperature;

C. and then make sample be warming up to 30 ℃, and under this temperature, be retained to vacuum and change when little, be incubated 1 hour and finish whole freeze-drying process.

Embodiment 4

Prescription: (1000 bottles, dosage is for containing diisopropylamine dichloroacetate 80mg and gluconic acid sodium salt 76mg)

Diisopropylamine dichloroacetate 80g

Gluconic acid sodium salt 76g

Water for injection 1000ml

Preparation technology:

1. under cleaning condition, get freshly prepd water for injection (80% amount of writing out a prescription approximately), cool the temperature to below 40 ℃, add the diisopropylamine dichloroacetate and the gluconic acid sodium salt of recipe quantity, stir and make dissolving;

2. press the needle-use activated carbon of amount of preparation adding 0.2%, stirring and adsorbing 45 minutes, filtering decarbonization;

3. add water for injection below 40 ℃ to recipe quantity, stir evenly, with 0.22 μ m filtering with microporous membrane degerming;

4. press every bottle of fill of 1ml/ in cillin bottle, place freeze dryer, carry out lyophilization by following freeze-dry process:

A. be cooled to-50 ℃ with 1 ℃ of per minute, be incubated 4 hours, make sample be warming up to-30 ℃ again per hour to heat up 2 ℃, keeping about 1 hour under this temperature, and then be cooled to-50 ℃, be incubated 4 hours with 1 ℃ of per minute; So repeat pre-freeze 3 times;

B. again evacuation to make vacuum be 10Pa, per hour heating up 2 ℃ makes sample be warming up to-30 ℃, and carries out primary drying 30 hours under this temperature;

C. and then make sample be warming up to 25 ℃, and under this temperature, be retained to vacuum and change when little, be incubated 1 hour and finish whole freeze-drying process.

Claims (6)

1, a kind of compound diisopropylamine dichloroacetate lyophilized formulations that does not contain adjuvant is characterized in that: only contain medicine diisopropylamine dichloroacetate and gluconic acid sodium salt in its preparation, and do not contain any additive.

2, according to claims 1 described a kind of compound diisopropylamine dichloroacetate lyophilized formulations that does not contain adjuvant, it is characterized in that:

Contain diisopropylamine dichloroacetate 2mg ~ 200mg and gluconic acid sodium salt 1.9mg ~ 190mg in the lyophilized formulations of a dosage.

3, according to claims 1 described a kind of compound diisopropylamine dichloroacetate lyophilized formulations that does not contain adjuvant, it is characterized in that:

The weight ratio of described diisopropylamine dichloroacetate and gluconic acid sodium salt is 1:0.95.

4, a kind of preparation technology who does not contain the compound diisopropylamine dichloroacetate lyophilized formulations of adjuvant, it is characterized in that: the ratio of preparation technology's Chinese medicine and water is 1:1 ~ 100.

5, according to claims 4 described a kind of preparation technologies that do not contain the compound diisopropylamine dichloroacetate lyophilized formulations of adjuvant, it is characterized in that: prepare medicinal liquid earlier, adopt one or many pre-freeze distillation freeze drying technology technology to be prepared again.

6, according to claims 5 described a kind of preparation technologies that do not contain the compound diisopropylamine dichloroacetate lyophilized formulations of adjuvant, it is characterized in that preparation technology is:

(1) under cleaning condition, get freshly prepd water for injection, cool the temperature to below 40 ℃, add the diisopropylamine dichloroacetate and the gluconic acid sodium salt of recipe quantity, stir and make dissolving;

(2) add 0.05 ~ 1% needle-use activated carbon by amount of preparation, stirring and adsorbing 10 ~ 60 minutes, filtering decarbonization;

(3) add water for injection below 40 ℃ to recipe quantity, stir evenly the degerming of reuse filtering with microporous membrane;

(4) after the fill according to dosage, place freeze dryer, carry out lyophilization by following freeze-dry process:

A. be cooled to-15 ~-70 ℃, per minute falls 1 ~ 2 ℃, is incubated 2 ~ 5 hours, makes sample be warming up to-10 ~-30 ℃ again, per hour heat up 2 ~ 5 ℃, keeping about 1 hour under this temperature, and then be cooled to-15 ~-70 ℃, per minute falls 1 ~ 2 ℃, is incubated 2 ~ 5 hours, so repeats pre-freeze 0 ~ 3 time;

B. again evacuation to make vacuum be 0.01 ~ 200Pa, make sample be warming up to-10 ~-30 ℃, per hour heat up 2 ~ 5 ℃, and under this temperature, carried out primary drying 2-50 hour;

C. and then make sample be warming up to 10 ~ 30 ℃, and under this temperature, be retained to vacuum and change when little, be incubated 1 hour and finish whole freeze-drying process.