CN111821260B

CN111821260B - Process for the manufacture of medicaments for suspension

Info

Publication number: CN111821260B
Application number: CN202010622019.5A
Authority: CN
Inventors: 卢朝成; 廖成斌; 吴仕炜; 刘圣梅
Original assignee: Chengdu Zhongmu Biological Pharmaceutical Co Ltd
Current assignee: Chengdu Zhongmu Biological Pharmaceutical Co Ltd
Priority date: 2020-06-30
Filing date: 2020-06-30
Publication date: 2022-04-01
Anticipated expiration: 2040-06-30
Also published as: CN111821260A

Abstract

The invention relates to the technical field of veterinary drug production, in particular to a production method for a suspension drug, which comprises the following steps: (1) the preparation method of the suspending agent comprises the following steps: dissolving and swelling sodium alginate in water to obtain a sodium alginate solution; (2) component mixing step: and then mixing the iodoethersalicylamide, the auxiliary agent and the sodium alginate solution in water for homogenization. The method uses the swollen sodium alginate as a thickening agent and a suspending agent to solve the technical problems that the iodoethersalicylamide suspension is easy to precipitate and layer and the medicament is easy to harden after layering. The scheme can be applied to the production of iodoethersalicylamide mixed suspension and the treatment of diseases such as livestock fasciola hepatica and the like.

Description

Process for the manufacture of medicaments for suspension

Technical Field

The invention relates to the technical field of veterinary drug production, in particular to a production method for a suspension drug.

Background

The iohersil is off-white to brown powder, is soluble in acetone, slightly soluble in chloroform or ethyl acetate, slightly soluble in methanol, and insoluble in water. The iodoethersalicylamide is a veterinary drug for resisting helminthiasis, has an anti-fasciolopsis effect, and has an uncoupling effect on the mitochondrial oxidative phosphorylation process of the worm body by transferring cations across cell membranes, so that the energy metabolic process of the worm body is influenced, and the worm body is killed. For ease of administration, the iodoethersalicylamide is typically prepared in the form of a suspension for oral administration to the animal. In addition to being convenient for feeding animals, the form of the suspension has higher bioavailability of the drug in the suspension and enables the iohexosamine to exert the drug effect more quickly. However, due to the water-insoluble property of the iohexosamine, the iohexosamine cannot be stably dispersed in a suspension system (in safety consideration, the suspension generally adopts water as a solvent), and after long-term storage, the iohexosamine suspension is easy to precipitate and layer, and the medicament is easy to harden after layering and is not easy to disperse again, so that the medicament effect is seriously influenced. The development of a production method for preparing stable iodoethersalicylamide suspension is urgently needed to solve the technical problem that the iodoethersalicylamide suspension is easy to precipitate and layer.

Disclosure of Invention

The invention aims to provide a production method for a medicament used for suspension, which uses swelled sodium alginate as a thickening agent and a suspending agent to solve the technical problems that the iodothersalamide suspension is easy to precipitate and delaminate, and the medicament is easy to harden after delamination.

In order to achieve the purpose, the invention adopts the following technical scheme:

a process for the manufacture of a medicament for suspension comprising the steps of:

(1) the preparation method of the suspending agent comprises the following steps: dispersing and swelling sodium alginate in water to obtain a sodium alginate solution;

(2) component mixing step: mixing the iodoethersalicylamide, the auxiliary agent and the sodium alginate solution in water, and homogenizing.

The principle and the advantages of the scheme are as follows: iohexosamine (CAS NO.22662-39-1) is an off-white to brown powder, soluble in acetone, sparingly soluble in chloroform or ethyl acetate, sparingly soluble in methanol, and insoluble in water. The iodoethersalicylamide can be quickly settled in water to be hardened, and a suspending agent and a thickening agent are required to be added into the iodoethersalicylamide, so that the iodoethersalicylamide can be stably dispersed in a suspension, and the medicine is uniform and convenient to administer. After the sodium alginate absorbs water and swells, the viscosity of a dispersion medium can be increased so as to reduce the sedimentation speed of the iodoethersalicylamide particles. The sodium alginate is a natural polymer material, molecules of the sodium alginate are fully expanded in water after swelling, and groups on the molecules interact with the iodoethersalicylamide particles through intermolecular force, so that the iodoethersalicylamide can be uniformly dispersed in the aqueous solution of the sodium alginate. Sodium alginate can form a protective barrier of the iohexosamine, prevent or reduce attraction or flocculation between iohexosamine particles, and maintain a relatively uniform dispersion state of the iohexosamine particles. Among them, swelling is a phenomenon in which a high molecular polymer expands in volume in a solvent.

The inventors have tried a number of different suspending agents and thickening agents, none of which achieve the goal of stable dispersion of the iodothersalamide in the suspension system (e.g., sodium carboxymethylcellulose, xanthan gum, starch, polyethylene glycol, dextran, etc.). The suspending effect of the sodium alginate is better than that of other suspending agents, and the iodoethersalicylamide mixed suspension can be stably stored for a long time without layering. Even if the iodothersalamide suspension is layered, the uniform re-dispersion of the iodothersalamide can be realized by slightly shaking the medicine bottle. The inventor analyzes the reason that sodium alginate has a certain function of a surfactant, has good adaptability to the medicament of the iohexosamine, can reduce the surface tension of iohexosamine medicament particles, promotes the fusion of the medicament and an aqueous solution, increases the sedimentation volume ratio within a specified time, and prolongs the sedimentation time of the medicament.

Further, the auxiliary agent comprises dimethyl silicone oil, vegetable oil, a preservative, a surfactant, a flocculating agent and a deflocculating agent.

By adopting the technical scheme, the dimethicone can improve the surface activity of the sodium alginate, so that the iodoethersalicylamide can be stably suspended in the suspension. The vegetable oil can partially replace the dimethyl silicone oil, so that the cost is reduced; the surfactant is a surfactant which has two opposite properties of lipophilicity and hydrophily in a molecule, and can reduce the surface tension of the drug particles, so that the iodoethersalicylamide particles can be fully wetted by water, can interact with a suspending agent and the like, and prevent the particles from settling and agglomerating. The suspension contains a large amount of oil phase and medicament, and if a surfactant is not used, the oil phase cannot be uniformly dispersed, so that oil and water can be separated.

Further, the vegetable oil is one of soybean oil, sunflower seed oil, corn oil and rapeseed oil or mixed oil formed by more than two vegetable oils; the preservative is one or a mixture of more than two of benzyl alcohol, sorbic acid, benzoic acid, methyl paraben and ethyl paraben; the surfactant is a nonionic surfactant; the flocculating agent is citric acid; the deflocculant is sodium citrate.

By adopting the technical scheme, the ionic surfactant can change a system charge system and destroy the original suspension system, so that the nonionic surfactant is required to be adopted. Citric acid and sodium citrate are respectively used as flocculating agent and deflocculating agent, and can also play a role in adjusting and buffering pH value, and simultaneously, the citric acid and the sodium citrate can also be used as preservative of the suspension medicine.

Further, in the step (1), dispersing sodium alginate in water, and then standing at room temperature for 12h to obtain a sodium alginate solution; or dispersing sodium alginate in 70-100 deg.C water, and standing in water for 2 hr to obtain sodium alginate solution.

By adopting the technical scheme, the sodium alginate is a high-molecular material, the swelling time of the sodium alginate needs to be ensured, and the sodium alginate can be used after being dissolved to form a uniform solution. If sodium alginate is not sufficiently swollen, its suspending effect is impaired.

Further, in the step (2), firstly, dissolving tween-80 in water to obtain a tween solution; dispersing the iodoethersalicylamide in a tween solution, then adding the soybean oil, the simethicone and the benzyl alcohol, stirring uniformly, then adding the sodium alginate solution, and mixing uniformly again to obtain a mixed solution; and adding a citric acid solution and a sodium citrate solution into the mixed solution, uniformly mixing, and adding water to a set volume to obtain the suspension medicine.

By adopting the technical scheme, the iodoethersalicylamide is added into the tween-80 after the tween-80 is dissolved, otherwise, the medicament is not easy to disperse and wet and can float on the liquid surface; during the process of adding the oil phase (soybean oil and dimethyl silicone oil), the oil phase and the water phase are preferably added while stirring, so as to accelerate the uniform mixing of the oil phase and the water phase; the sodium alginate solution needs to be added at last, and because the sodium alginate has certain viscosity, the sodium alginate is added too early, and other components are not easy to be mixed uniformly.

Further, after adding a citric acid solution and a sodium citrate solution into the mixed solution, homogenizing the mixed solution under the pressure of 30mpa, and adding water to a set volume after uniformly mixing.

By adopting the technical scheme, the homogenization treatment is carried out under the pressure of 30mpa, so that the particle size of the material is reduced and uniform, the liquid medicine is mixed more fully and uniformly, and the suspension lasts for a long time.

Further, the mass ratio of the iodoethersalicylamide to the sodium alginate is 100:1-5: 1.

By adopting the technical scheme, the iodoethersalicylamide suspension with stable property can be compounded. The dosage of the sodium alginate is too low, and the suspension effect is weakened; the sodium alginate has high dosage and good suspension effect, but the liquid is too viscous and has poor fluidity, so that the use is inconvenient (the viscosity is too high and continuous administration can not be realized by a syringe), the suspension is also sticky to a bottle, and the medicament loss is too large. The iodoethersalicylamide and the sodium alginate are in an inverse relationship, and when the concentration of the iodoethersalicylamide is higher, the suspending agent dosage required for uniformly mixing the iodoethersalicylamide and the sodium alginate to form a suspension is reduced.

Furthermore, 1-10kg of iodoethersalicylamide is contained in each 100L of suspension medicine.

By adopting the technical scheme, sodium alginate is used as a suspending agent, so that stable suspension of the iodoethersalicylamide with the concentration is realized.

Further, every 100L of the suspension medicine contains more than or equal to 7L of simethicone.

By adopting the technical scheme, the simethicone with the dosage can play a role in preventing the hardening of the suspension and enhancing the suspending effect of the sodium alginate on the iodoethersalicylamide.

Further, the pH value of the suspension medicine is 5.5-5.8.

By adopting the technical scheme, the pH value can better maintain the suspension state of the medicament and the pharmacological activity of the medicament.

Detailed Description

Example 1: preparation of iodoethersalicylamide suspension

The formula of the iodoethersalicylamide suspension is as follows: each 100L of suspension medicine contains 2kg of iodoethersalicylamide (oral grade, CAS NO.22662-39-1), 225g of sodium alginate (analytically pure, CAS NO.9005-38-3), 10kg of tween-80 (analytically pure, CAS NO.9005-65-6), 100g of citric acid (oral grade, CAS NO.77-92-9), 100g of sodium citrate (oral grade, CAS NO.68-04-2), 3L of soybean oil (food grade, CAS NO.8001-22-7), 7L of simethicone (food grade, CAS NO.9006-65-9), 1000ml of benzyl alcohol (analytically pure, CAS NO.100-51-6), and the balance of water (distilled water or water for injection). The sodium alginate used in the scheme is a high polymer material, and the viscosity of the sodium alginate needs to be checked according to the requirements of GB 1886.243-2016 national standard for food safety food additive sodium alginate, and the viscosity can be used in the formula within 600-800.

The preparation process of the iodoethersalicylamide suspension comprises the following steps (preparing 100L of suspension medicine):

1. dissolving sodium alginate in the formula amount with 20L of distilled water, and standing for 12h to swell the sodium alginate to obtain sodium alginate solution for use.

2. The tween-80 is dissolved in 20L of distilled water to obtain a tween solution for use (a nonionic surfactant is required, in this case, other nonionic surfactants can be used to replace tween-80, for example, the nonionic surfactant can be one or a mixture of more than two of poloxamer, tween-60 and tween-80).

3. Adding the iodoethersalicylamide with the formula amount into the Tween solution, uniformly stirring, adding the soybean oil, the simethicone and the benzyl alcohol with the formula amount, uniformly stirring, adding the sodium alginate solution, and uniformly stirring again to obtain a mixed solution.

4. And (3) dissolving citric acid and sodium citrate in distilled water respectively, adding the dissolved citric acid and sodium citrate into the mixed solution obtained in the step (3), and homogenizing twice by using a high-pressure homogenizer at the pressure of 30 mpa.

5. The iohexosamine suspension of this example was obtained by adding distilled water to approximately the full volume (100L) and adjusting the pH to 5.8 (generally, the pH was adjusted to 5.5-5.8, or optionally, the pH was not adjusted).

The mass ratio of the iohexosamine to the sodium alginate can be 100:1-2:1, but in order to control the viscosity (so that the fluidity of the suspension is better), the mass ratio of the iohexosamine to the sodium alginate is controlled to be 100:1-5: 1. In the scheme, 2kg of iodothersalamide and 225g of sodium alginate (namely 8.89:1) are specifically selected to be contained in each 100L of suspension medicine.

Example 2 is essentially the same as example 1, except that the formulation ingredients were changed (as shown in Table 1) and water swelling of sodium alginate at 70 deg.C for 2h was used in making the sodium alginate solution. Examples 3 to 5 are basically the same as example 1 except for the adjustment of the formulation and process parameters, as shown in Table 1.

Comparative examples 1 to 5 are substantially the same as in example 1, except for the adjustment of the formulation and process parameters, as shown in Table 2. In comparative examples 1 to 5, the amounts of the suspending agent (thickener) such as sodium carboxymethylcellulose, xanthan gum (dextran-70 complex), starch (dextran-20 complex), polyvinyl alcohol and dextran were all the optimum amounts obtained after many experimental tests.

Comparative example 6-comparative example 10 are substantially the same as example 1 except for the adjustment of the formulation and process parameters, as shown in table 3.

Comparative example 11 is substantially the same as example 1 except that after dispersing sodium alginate in water, there is no time left for the sodium alginate to swell and proceed directly to the next step. Comparative example 12 is substantially the same as example 1 except that the iodoethersalicylamide was dispersed in water to obtain an iodoethersalicylamide dispersion, tween-80 was added to the iodoethersalicylamide dispersion and stirred uniformly, then soybean oil, simethicone and benzyl alcohol in the formula amounts were added and stirred uniformly, then the sodium alginate solution was added and stirred uniformly again to obtain a mixed solution.

Table 1: example parameter setting conditions List (example 1-example 5)

Table 2: comparative example parameter setting case list (comparative example 1 to comparative example 5)

Table 3: comparative example parameter setting case list (comparative example 6-comparative example 10)

Experimental example 1

Sedimentation volume ratio: the sedimentation volume ratios of examples 1 to 5 and comparative examples 1 to 12 (10 replicates were set for each example or comparative example, n is 10) were measured by referring to the method for measuring the sedimentation volume ratio in 0111 oral solution, oral suspension and oral emulsion, first edition of chinese animal pharmacopoeia 2015, and the larger the sedimentation volume ratio for a given sedimentation time (3 h, 24h, 48h and 7 days, four sedimentation times are used in this experimental example), the better and more stable the suspension effect of the suspension is, and the experimental results are shown in tables 4 to 6.

And (3) detecting the redispersion condition: 500ml of the suspension in the above examples and comparative examples was taken, placed in a sample bottle (repeat experiment was not set), left to stand for three months (different degrees of delamination occurred in each case), and the sample bottle was inverted upside down, and it was observed how many times the delaminated suspension was inverted and re-dispersed, and the suspension was not re-dispersed even if the number of inversion exceeded 20 times, and the experiment results were as shown in tables 4 to 6, assuming that the sample was not re-dispersed.

Table 4: results of measurement (example 1 to example 5, sedimentation volume ratio is expressed in mean ± SD, n ═ 10)

Table 5: results of measurement (comparative examples 1 to 6, sedimentation volume ratio is expressed in mean ± SD, n ═ 10)

Table 6: results of measurement (comparative examples 7 to 12, sedimentation volume ratio is expressed in mean ± SD, n ═ 10)

According to the experimental results in tables 4 to 6, it can be known that the iohexosamine suspension obtained in examples 1 to 5 by adopting the formula and the preparation process of the scheme has better stability, sodium alginate has excellent suspension effect on iohexosamine, and the use of simethicone can promote the stability of the whole suspension and promote the redispersion of the suspension after delamination. The sedimentation volume ratios of the examples 1 to 5 at the respective sedimentation times are significantly different from those of the comparative examples 2 to 7 and 10 by statistical examination. In comparative examples 1 to 5, the inventors used different suspending agents (thickeners) to suspend the iohexosamine, and found that the above-mentioned treatment methods did not provide a good suspending effect, and that the iohexosamine-containing suspensions were still prone to drug precipitation delamination and drug hardening after precipitation delamination. Comparative example 6 reduced the amount of dimethicone, comparative example 7 and comparative example 8 did not use dimethicone, and comparative example 8 did not use sodium alginate. The result shows that the suspension effect is poor, and the suspension is easy to separate and not easy to redisperse due to the small dosage of the dimethyl silicone oil or no use of the dimethyl silicone oil. The sodium alginate and the dimethyl silicone oil are used in a matching way, so that the suspension effect on the medicine can be improved, and the medicine is easy to disperse again after being layered. In addition, comparative examples 1 and 8, in which sodium carboxymethylcellulose was used as a suspending agent, the sample liquid medicine was rapidly divided into three layers, the powder was solidified in a bean-flower shape, and the sedimentation volume ratio could not be measured (in the specific case: the suspension liquid medicine was divided into three layers, the powder and the oil phase floated on the upper layer, the powder layer on the lower layer, and the aqueous solution layer in the middle). The amount of sodium alginate used in comparative example 9 was too low, and the suspending effect was weak. Comparative example 10 used too high amount of sodium alginate, and the suspension was very good, but the liquid was too viscous and the fluidity was not good, which resulted in inconvenient use (too high viscosity for continuous administration by syringe), and also resulted in sticking of the suspension into a bottle and excessive loss of the drug. The iodoethersalicylamide and the sodium alginate are in an inverse relationship, and when the concentration of the iodoethersalicylamide is higher, the suspending agent dosage required for uniformly mixing the iodoethersalicylamide and the sodium alginate to form a suspension is reduced. The sodium alginate of comparative example 11 did not swell sufficiently, the suspending effect became poor, and the dispersion was not uniform. In comparative example 12, tween-80 was not first formulated into a solution before tween-80 and the drug were mixed. Thus, the drug is not easily dispersed and wetted and will float on the surface of the liquid.

The foregoing is merely an example of the present invention and common general knowledge of known specific structures and features of the embodiments is not described herein in any greater detail. It should be noted that, for those skilled in the art, without departing from the structure of the present invention, several changes and modifications can be made, which should also be regarded as the protection scope of the present invention, and these will not affect the effect of the implementation of the present invention and the practicability of the patent. The scope of the claims of the present application shall be determined by the contents of the claims, and the description of the embodiments and the like in the specification shall be used to explain the contents of the claims.

Claims

1. A process for the manufacture of a medicament for suspension, comprising the steps of:

(2) component mixing step: dissolving tween-80 in water to obtain tween solution, dispersing iodoethersalicylamide in the tween solution, sequentially adding the auxiliary agent and the sodium alginate solution, and mixing and homogenizing; the auxiliary agent comprises dimethyl silicone oil;

the mass ratio of the iodoethersalicylamide to the sodium alginate is 100:1-5: 1; the medicine suspension contains 1-10kg of iodoethersalicylamide per 100L of medicine suspension.

2. The process for the manufacture of a medicament for suspension according to claim 1 wherein said adjuvants include vegetable oils, preservatives, flocculants and deflocculants.

3. The method for producing a suspension medicament as claimed in claim 2, wherein said vegetable oil is one or a mixture of two or more of soybean oil, sunflower oil, corn oil and rapeseed oil; the preservative is one or a mixture of more than two of benzyl alcohol, sorbic acid, benzoic acid, methyl paraben and ethyl paraben; the flocculating agent is citric acid; the deflocculant is sodium citrate.

4. The production method for a suspension medicament as claimed in claim 3, wherein in the step (1), sodium alginate is dispersed in water and then left to stand at room temperature for 12 hours to obtain a sodium alginate solution; or dispersing sodium alginate in 70-100 deg.C water, and standing in water for 2 hr to obtain sodium alginate solution.

5. The process for preparing the suspension medicine according to claim 4, wherein in the step (2), the process of adding the auxiliary agent and the sodium alginate solution in sequence, mixing and homogenizing is as follows: dispersing the iodoethersalicylamide in a tween solution, adding soybean oil, simethicone and benzyl alcohol, stirring uniformly, adding a sodium alginate solution, and mixing uniformly to obtain a mixed solution; and adding a citric acid solution and a sodium citrate solution into the mixed solution, uniformly mixing, and adding water to a set volume to obtain the suspension medicine.

6. The method for manufacturing a suspension medicament as claimed in claim 5, wherein after the citric acid solution and the sodium citrate solution are added to the mixed solution, the mixed solution is homogenized under the pressure of 30mpa, and after the homogenization, water is added to a set volume.

7. The process for the production of a drug suspension according to any one of claims 1 to 6, characterized in that it comprises greater than or equal to 7L of simethicone per 100L of drug suspension.

8. The process for the manufacture of a medicament for suspension according to claim 7 wherein the pH of the suspension medicament is between 5.5 and 5.8.