CN113908114A - Flugesterone acetate vaginal sponge - Google Patents

Abstract

The invention provides a fluogesterone acetate sponge, which consists of liquid medicine and sponge, wherein the raw materials of the liquid medicine comprise fluogesterone acetate, suspending agent hydroxypropyl methylcellulose K100M, polyethylene glycol 6000 and bacteriostatic agent; wherein the liquid medicine uses water as solvent. The fluoprogesterone acetate sponge is suitable for full-automatic filling production, and can effectively improve preparation efficiency and product quality.

Description

Flugesterone acetate vaginal sponge

Technical Field

The invention belongs to the technical field of veterinary medicines, and particularly provides a fluoprogesterone acetate sponge suitable for full-automatic filling production.

Background

China is a sheep breeding big country, the sheep breeding amount exceeds 3 hundred million according to 2020 data of the State statistics office, but the development of related technologies of the sheep breeding industry at present lags behind abroad relatively, and the development of the sheep breeding industry needs to refer to corresponding technologies in the pig breeding industry, such as batch production technology, namely, the breeding of pigs is similar to the batch and scale production of food/medicines produced by factories, so that the pork quality (food safety and pork quality) is improved, the production efficiency is also improved, and the resource waste is also reduced to a certain extent. Similarly, batch production is realized in the sheep raising industry, wherein the most key link is the sheep breeding link, and batch fattening and batch marketing of the mutton sheep can be realized only if batch breeding is presented.

In the batch breeding link of ewes, the current mainstream technology at home and abroad is to adopt progestogen (flurogest acetate vaginal sponge suppository, medroxyprogesterone acetate sponge suppository and progesterone vaginal sustained release agent) to induce ewes to realize batch synchronous estrus, so that batch timed insemination (timed insemination) mating and batch delivery are carried out, the ewes after delivery are batched weaned, so that progestogen is reused to induce batch synchronous estrus, and the weaned ewes are batched fattened, so that batch production is realized.

Fluogesterone acetate vaginal sponge is a veterinary drug, i.e. a certain amount of fluogesterone acetate (an artificially synthesized progestogen analogue) is loaded into a polyurethane sponge, thus forming the final product. The product is mainly used for the estrus synchronization of female animals. The sponge used in the product is generally cylindrical, with a ground diameter of 3-4cm and a height of 3-6 cm. After the female animals are treated by the product, the fluogesterone acetate in the sponge is gradually and slowly released in the vagina of the female animals so as to exert the drug effect, which is generally called as follows in the field of domestic and foreign veterinary drugs: controlling the Internal Drug release device (Controlled Internal Drug Releasing). The action process is as follows: after the fluogesterone acetate vaginal sponge is placed into the vagina, the fluogesterone acetate is slowly released from the sponge (a large number of pores are arranged on the sponge) and absorbed into the body through vaginal mucosa, so that the concentration of the fluogesterone acetate in blood plasma is kept at a normal effective concentration, and the secretion of pituitary gonadotropin and hypothalamic gonadotropin releasing hormone is inhibited through a feedback mechanism, thereby inhibiting estrus and ovulation and artificially prolonging the luteal phase. Once the vaginal sponge of fluogesterone acetate is taken out, the concentration of the fluogesterone acetate is reduced, the effect is disappeared, the pituitary of the animal restarts to secrete gonadotropin again, and the growth of the follicle and the estrus of the animal are promoted.

The flurogestone acetate vaginal sponge suppository used in induced batch estrus synchronization of ewes belongs to a veterinary drug, and the currently disclosed production modes are all manual production, so that the efficiency is low, and the related requirements of the veterinary drug GMP cannot be met. According to the information in patent and literature documents, the traditional fluogesterone acetate vaginal sponge is simpler in prescription, and organic solvents such as ethanol, acetone and oil solvents are generally selected; and then, dissolving the fluoprogesterone acetate in an organic solvent or grease, and then filling the fluoprogesterone acetate-organic solvent liquid medicine into the sponge, wherein the risk of liquid medicine leakage can occur in the process (the sponge is made of polyurethane or polyether, organic matter is a porous structure, a large number of pores are distributed on the surface, organic solvents such as ethanol and acetone are easy to actively permeate through the sponge), and the key quality standards such as product content and the like are unqualified (the key quality standards cannot reach the limit specified by national standards) due to liquid medicine leakage.

Disclosure of Invention

In order to solve the above problems, the applicant has designed a novel formulation of flurogestone acetate vaginal sponge that can be adapted to automated production.

On one hand, the application provides a fluogesterone acetate vaginal sponge, which is characterized in that the fluogesterone acetate vaginal sponge consists of liquid medicine and sponge, and the raw materials of the liquid medicine comprise fluogesterone acetate, a suspending agent and a bacteriostatic agent.

Further, the suspending agent is at least one selected from hydroxypropyl methylcellulose, polyethylene glycol 4000, polyethylene glycol 6000, povidone K60, lanolin, methylcellulose and carboxymethyl cellulose.

Further, the suspending agent is hydroxypropyl methylcellulose K100M and polyethylene glycol 6000.

Further, the bacteriostatic agent is at least one of chlorhexidine acetate, chlorhexidine gluconate, methyl paraben (sodium), ethyl paraben (sodium), propyl paraben (sodium), butyl paraben, cetrimide and dodecyl trimethyl ammonium bromide.

Further, the bacteriostatic agent is methyl paraben and propyl paraben.

Furthermore, the medicinal liquid raw materials of the fluogesterone acetate vaginal sponge are fluogesterone acetate, hydroxypropyl methylcellulose K100M, polyethylene glycol 6000, methyl paraben, propyl paraben and water.

Furthermore, the liquid medicine of the fluoprogesterone acetate vaginal sponge comprises 30-50mg of fluoprogesterone acetate, 20-40mg of hydroxypropyl methylcellulose K100M 20, 600020-80 mg of polyethylene glycol, 0.5-3mg of methyl paraben, 0.1-2mg of propyl paraben and 0.5-5mL of water; wherein the grain size D90 of the fluogesterone acetate is less than or equal to 100 mu m.

Furthermore, the liquid medicine of the fluogesterone acetate vaginal sponge comprises 40mg of fluogesterone acetate, 100 mg of hydroxypropyl methylcellulose K100M 30mg, 600050 mg of polyethylene glycol, 1.5mg of methyl hydroxybenzoate, 0.5mg of propyl hydroxybenzoate and 1.95mL of water; wherein the grain size D90 of the fluogesterone acetate is 40-60 μm.

Further, the preparation process of the fluogesterone acetate vaginal sponge comprises the steps of liquid medicine preparation and filling.

Further, the liquid medicine preparation steps are as follows:

adding a proper amount of water with the temperature of 60 ℃ into a mixing tank, keeping the water bath heating, adding hydroxypropyl methylcellulose K100m with the formula amount, and uniformly stirring; adding polyethylene glycol-4000 in the amount of the prescription, and uniformly stirring; adding the formulated amount of fluoprogesterone acetate, methyl paraben and propyl paraben, and stirring to uniformly suspend the mixture; adding the rest water with the temperature of 30 ℃; continuously stirring until the liquid medicine is stably recovered to the room temperature; the viscosity of the detection liquid medicine should be 350-450 cps.

The filling steps are as follows:

transferring the buffer tank to a vaginal sponge filling room, and adjusting the filling amount of a filling machine to be 1.95-2.05 ml; and taking out the cleaned and dried sponges, placing the sponges on a filling line, filling and adding chemicals to each sponge, immediately transferring the filled sponges to a product drying room, and drying the sponges to constant weight by air blowing at a drying temperature of 80 +/-5 ℃.

Advantageous effects

The liquid medicine of the invention takes water as solvent, is added with suspending agent to prepare fluoprogesterone acetate suspension, and then is filled on a blank spongy suppository. In the filling process, the liquid medicine can be accurately and uniformly filled on the sponge under the dynamic stirring state. Sponge plugs, although they exhibit a number of pores, do not absorb water actively, usually passively, e.g. the sponge is squeezed in water and soon absorbs water completely to saturation. When the liquid medicine is filled, the filling needle is inserted into the sponge to complete filling, and the filling volume is 1.9ml-2.1 ml; the liquid medicine is a suspension, has certain viscosity of about 400 +/-50 cps, so that the liquid medicine has poor fluidity in the sponge suppository, cannot leak, and cannot leak after the sponge suppositories filled with the liquid medicine are mutually extruded, but the liquid medicine is fully distributed in the inner porous space of the sponge suppository. Therefore, the prescription can realize automatic and efficient filling production.

Drawings

Fig. 1 is a diagram of a sponge plug according to the present application.

Detailed Description

EXAMPLE 1 preparation of Flugesterone acetate sponge suppository

Sponge shape and size: a cylindrical polyurethane sponge;

size: diameter 3.7cm, height: 3.0 cm;

color: white colour

Consists of the following components: polyurethane sponge, fluoprogesterone acetate and auxiliary materials (suspension and preservative)

Fluogesterone acetate: main active ingredient, particle size: d90 ≦ 100 μm, preferably 40-60 μm (to avoid dissolution or sedimentation)

Auxiliary materials:

suspending agent: at least one selected from hypromellose, polyethylene glycol 4000, polyethylene glycol 6000, polyvinylpyrrolidone K60, lanolin, methylcellulose, carboxymethylcellulose, etc., and hypromellose K100M and polyethylene glycol 6000 are preferred in the present invention. The dosage proportion is as follows: hydroxypropyl methylcellulose K100m, the conventional dosage is 0.05-10%, and the optimal dosage is 1.5%; polyethylene glycol 4000, conventionally used in amounts of 0.5% to 20%, preferably 2.5% in the present invention.

Bacteriostatic agent: the bacteriostatic agent of the preparation for intravaginal administration is at least one selected from chlorhexidine acetate, chlorhexidine gluconate, methyl (sodium) p-hydroxybenzoate, ethyl (sodium) p-hydroxybenzoate, propyl (sodium) p-hydroxybenzoate, butyl p-hydroxybenzoate, cetrimide, dodecyl trimethyl ammonium bromide and the like, and the methyl p-hydroxybenzoate and the propyl p-hydroxybenzoate are preferred in the invention.

Preparing a fluoprogesterone acetate liquid medicine:

adding appropriate amount of 60 deg.C water (keeping heating in water bath), adding hydroxypropyl methylcellulose K100m, and stirring. Adding the polyethylene glycol-4000 with the prescription amount, and uniformly stirring. Then adding the bacteriostatic agent according to the prescription amount, adding the fluoprogesterone acetate, the methyl paraben and the propyl paraben according to the prescription amount, and stirring to uniformly suspend the mixture. Finally, water at 30 ℃ is added to the mark. Stirring is continued until the liquid medicine is stably recovered to the room temperature. The viscosity of the detection liquid medicine should be 350-450 cps.

Filling:

before production, checking according to 'inspection management system before workshop production', and confirming that each post is within the clear yard validity period and has a clear yard qualification certificate; the equipment and the container are cleaned and in the valid period.

And (4) transferring the buffer tank to a vaginal sponge filling room, and adjusting the filling amount of the filling machine to be 1.95-2.05 ml. And taking out the cleaned and dried sponges, placing the sponges on a filling line, filling and adding chemicals to each sponge, immediately transferring the filled sponges to a product drying room, and drying the sponges to constant weight by air blowing at a drying temperature of 80 +/-5 ℃.

Production efficiency: the previous production method produced approximately 2000 pieces of flurogestone acetate sponge plug per day, and now produced 35000 pieces 40000 pieces/day. The improvement is 17.5-20 times.

Example 2 prescription screening

Prescription screening 1

TABLE 1 prescription screening 1-Flugesterone acetate vaginal sponge composed of different adjuvants

The medicine liquid is prepared according to different prescriptions of the fluogesterone acetate vaginal sponge in the table 1, and the proper prescription is evaluated and screened mainly from the aspects of the settlement of the prepared medicine liquid, the leakage of the prepared medicine liquid from the sponge during filling, the release degree and the content uniformity of the filled and dried sponge suppository and the like. Different viscosity and different suspension effect are determined by different auxiliary material compositions.

Table 2 comparison of different fluoprogesterone acetate vaginal sponges in prescription screening 1

Note: in the suspension effect, + represents poor suspension effect, and + + + represents good suspension effect, and-represents no suspension condition.

The liquid medicine in the formula D is changed into clear solution before being filled, the clear solution is filled on the sea surface and then dried, ethanol volatilizes, the fluogesterone acetate is recrystallized in sponge (gaps), the grain size of the fluogesterone acetate after recrystallization is changed and is far larger than that of the original raw material medicine, so that the grain size is larger and is not easily dissolved and released by a release medium during a release degree test, and the release degree is lower and does not reach the release degree limit regulation (more than or equal to 75%).

Prescription screening 2

Table 3 prescription screening 2-Flugesterone acetate vaginal sponge composed of different suspending agent

The filling liquid medicine of the fluogesterone acetate vaginal sponge consisting of different suspending agents is produced according to the prescription in the table 3, and the proper prescription is evaluated and screened mainly from the aspects of settlement of the prepared liquid medicine, leakage from the sponge during filling, release degree (according to the method for detecting the release degree in the embodiment 5), content uniformity and the like after filling and drying of the sponge suppository. Different viscosity and different suspension effect are determined by different suspending agent compositions.

Table 4 prescription screening 2 comparison of Flugesterone acetate vaginal sponges with different prescriptions

In table 4, similar release effects can be achieved after filling the flurogestone acetate liquid medicine consisting of different suspending agents on the sponge, and two or more of the flurogestone acetate liquid medicines can be combined.

Prescription screening 3

Through the prescription screening 1, basic raw and auxiliary materials and composition proportions are screened, on the basis, the granularity of the fluogesterone acetate raw material medicines is screened, the situations of liquid medicines prepared by the raw material medicines with different granularities are compared, and indexes such as the content uniformity and the release rate (according to the method for detecting the release rate in the embodiment 5) of the fluogesterone acetate vaginal sponge after the liquid medicines are dried are compared. (different particle sizes determine whether the medicine can be suspended, the particle size is too fine, the medicine is dissolved and cannot achieve the suspension effect; the particle size is too large, the medicine is not easy to suspend and is easy to settle.)

TABLE 5 prescription screening 3-Fluoroprogesterone acetate particle size screening

TABLE 6 prescription screening 3-comparison of Flugesterone acetate vaginal sponges for different prescriptions

Experimental example 3 comparison of yield per production lot for two production modes

TABLE 7 comparison of the production efficiency of Flugesterone acetate vaginal sponges produced in different modes

EXAMPLE 4 Fluoroprogesterone acetate vaginal sponges prepared with sponges from different sources

The sponge with different sources and different materials is used for preparing the fluogesterone acetate sponge suppository according to the raw and auxiliary materials in the formula A1. The comparison was made in terms of release, content uniformity, etc.

TABLE 8 preparation of Flugesterone acetate vaginal sponges from sponges of different origins

	DG sponge	HT sponge	SZ sponge
				Raw and auxiliary materials	Prescription A1	Prescription A1	Prescription A1
Whether or not to leak	Whether or not	Whether or not	Whether or not
				Degree of release	88％	87％	89％
Content uniformity	Qualified	Qualified	Qualified
				Content (wt.)	Qualified	Qualified	Qualified

Example 5 comparison of pharmaceutical indices of Flugesterone acetate vaginal sponges

Content detection

The detection method is characterized in that octadecylsilane chemically bonded silica is used as a filling agent for 2017 Chinese veterinary drug quality standard chromatographic conditions and system applicability tests; acetonitrile-water (48:52) is used as a mobile phase; the detection wavelength was 240 nm. The number of theoretical plates is not less than 2000 calculated according to a fluogesterone acetate peak, and the separation degree of the fluogesterone acetate and an internal standard substance peak is in accordance with requirements.

Measurement of correction factor Diethylstilbestrol was dissolved in methanol and diluted to 0.8mg per 1ml, and shaken up to give an internal standard solution. Precisely weighing about 40mg of the norfluroxypyr reference substance, placing the norfluroxypyr reference substance into a 50ml measuring flask, adding methanol to dissolve and dilute the norfluroxypyr reference substance to a scale, and shaking up; precisely measuring 5ml, placing in a 25ml measuring flask, precisely adding 5ml of internal standard solution, adding methanol to dilute to scale, and shaking up; precisely measuring 10 μ l, injecting into a liquid chromatograph, and calculating correction factor.

Taking 1 product, adding 12ml of methanol, squeezing and extracting, transferring the extractive solution into a 100ml measuring flask, squeezing and extracting with methanol for 7 times, 10ml each time, mixing the extractive solution into the measuring flask, diluting with methanol to scale, and shaking; filtering, precisely measuring 10ml of the subsequent filtrate, placing the subsequent filtrate in a 25ml measuring flask, precisely adding 5ml of internal standard solution, diluting with methanol to scale, and shaking up; according to the method under the content determination item of the fluoprogesterone acetate, 10 mu l of the fluoprogesterone acetate is precisely measured and injected into a liquid chromatograph, and the correction factor is determined and calculated according to the method.

The result of the detection

TABLE 9 Flugesterone acetate vaginal sponge content test results

Batch number	Content detection result
		180321	99.6％
180323	100.5％
		180325	102.1％

Content uniformity

TABLE 10 Flugesterone acetate vaginal sponge content uniformity test results

As shown in the table, the content uniformity of the product is better, the standard deviation among products is smaller, and the product quality is more stable.

Degree of release

Octadecylsilane chemically bonded silica is used as a filler under chromatographic conditions; acetonitrile-water (48:52) is used as a mobile phase; the detection wavelength was 240 nm. The number of theoretical plates is not less than 2000 calculated according to the fluoprogesterone acetate peak.

Detection method

Preparation of test solution 1 vaginal sponge of fluogesterone acetate was taken, the sponge was fixed on a stainless steel holder, placed in a 250ml conical flask with a stopper, and 230ml of water preheated to 60 ℃ was added to immerse the sponge completely in the water without contacting the wall of the flask. The flask was placed in a constant temperature shaker preheated to 60 ℃ and the shaking speed was adjusted to 2.5 revolutions/second. After 24 hours, the sponge was removed and placed in another 250ml conical flask, and 230ml of water preheated to 60 ℃ was added to make the release rate the next day. 15ml of methanol was added to the solution remaining after the sponge was removed, cooled to room temperature, and quantitatively diluted to 250ml with water. Shaking thoroughly, filtering, and measuring the filtrate as test solution.

The determination method comprises precisely weighing appropriate amount of fluoprogesterone acetate reference, dissolving in acetonitrile, quantitatively diluting to obtain solution containing 0.4mg per 1ml, precisely weighing 2ml, placing in 50ml measuring flask, diluting with acetonitrile to scale, and shaking to obtain reference solution. Precisely measuring the reference solution and the sample solution by 20 μ l each, injecting into liquid chromatograph, and recording chromatogram. The daily release amount was calculated by peak area according to the external standard method. The total release was calculated by continuous measurement for 12 days. The limit is 75% of the indicated amount and should be met.

The result of the detection

TABLE 11 comparison of Release test results

Example 6 stability test

Three batches of the flurogestone acetate vaginal sponge were continuously produced according to the formulation a2 in example 1, and the production method, and stability studies were performed. Including accelerated stability testing and long-term stability testing.

Accelerated stability test (temperature 40 ℃ C. + -. 2 ℃ C., humidity 75% + -. 5%)

TABLE 12 accelerated stability test results for three batches of Flugesterone acetate vaginal sponges

Long term stability test (temperature 40 ℃ C. + -. 2 ℃ C., humidity 60% + -. 10%)

TABLE 13 Long-term stability test results for three batches of Flugesterone acetate vaginal sponges

Example 7 estrus synchronization

Healthy and mature barren ewes with 60 heads are selected and divided into two groups, and each group has 30 heads. Firstly, wiping, cleaning and disinfecting the pudendum of the ewe on the 1 st day of the test, then placing the sponge plug into a disinfecting and thrombus-releasing device, placing a pull wire at the rear end of the thrombus-releasing device, holding the thrombus-releasing device, coating anticorrosive lubricating oil outside the thrombus-releasing device, slightly placing an outer sleeve into the bottom of the ewe vagina along the longitudinal axis of the ewe vagina with the tip facing the longitudinal axis direction of the ewe vulva, slowly placing the outer sleeve inwards, slowly moving the outer sleeve, fixing the outer sleeve when the outer sleeve is blocked, pushing the vaginal plug into the bottom of the ewe vagina with an inner sleeve core, then pulling out the outer sleeve, and then pulling out the inner sleeve core. And (4) cutting off redundant traction wires on the vaginal suppository by using surgical scissors and keeping 4-5 cm. The day of suppository placement is 0 day, and the suppository is placed for 13 days. During the suppository placing period, the sheep flock is closely concerned every day, if the suppository is lost, the supplement is needed in time, and whether the oestrus performance of the ewes appears during the suppository placing period needs to be concerned. PMSG333 units were injected intramuscularly 48h before withdrawal of the embolus and PG 0.1mg was injected intramuscularly after withdrawal of the embolus.

One of the test drugs was the product of the present invention (test drug, prescription A2), and the control drug was Chronogram (MSD), PMSG (Ningbo second hormone plant), PG (Ningbo second hormone plant).

TABLE 14 results of estrus synchronization on ewes

The test effect of the test drug on the ewe for estrus synchronization shows that the test drug has equivalent effect to the control drug group, even has slightly excellent effect.

Claims (10)

1. The fluogesterone acetate vaginal sponge is characterized in that the fluogesterone acetate vaginal sponge consists of liquid medicine and sponge, and the raw materials of the liquid medicine comprise fluogesterone acetate, suspending agent and bacteriostatic agent.

2. The fluogesterone acetate vaginal sponge of claim 1, wherein the suspending agent is selected from at least one of hypromellose, polyethylene glycol 4000, polyethylene glycol 6000, povidone K60, lanolin, methylcellulose, carboxymethylcellulose.

3. The fluogesterone acetate vaginal sponge of claim 2, wherein the suspending agent is hypromellose K100M and polyethylene glycol 6000.

4. The fluogesterone acetate vaginal sponge of any of claims 1-3, wherein the bacteriostatic agent is at least one of chlorhexidine acetate, chlorhexidine gluconate, methyl (sodium) paraben, ethyl (sodium) paraben, propyl (sodium) paraben, butyl paraben, cetrimide, dodecyl trimethyl ammonium bromide.

5. The fluogesterone acetate vaginal sponge of claim 4, wherein the bacteriostatic agents are methyl paraben and propyl paraben.

6. The fluogesterone acetate vaginal sponge according to any one of claims 1-5, wherein the raw materials of the liquid medicine of the fluogestone acetate vaginal sponge are fluogestone acetate, hydroxypropyl methylcellulose K100M, polyethylene glycol 6000, methyl paraben, propyl paraben and water.

7. The fluoprogesterone acetate vaginal sponge of claim 6, wherein the liquid medicine of the fluoprogesterone acetate vaginal sponge comprises the raw materials of 30-50mg of fluoprogesterone acetate, 20-40mg of hydroxypropyl methylcellulose K100M 20, 600020-80 mg of polyethylene glycol, 0.5-3mg of methyl paraben, 0.1-2mg of propyl paraben and 0.5-5mL of water; wherein the grain size D90 of the fluogesterone acetate is less than or equal to 100 mu m.

8. The fluogesterone acetate vaginal sponge of claim 7, wherein the liquid medicine of the fluogesterone acetate vaginal sponge comprises 40mg of fluogesterone acetate, 100 mg of hydroxypropyl methylcellulose, 100M 30mg of polyethylene glycol, 600050 mg of polyethylene glycol, 1.5mg of methylparaben, 0.5mg of propylparaben and 1.95mL of water; wherein the grain size D90 of the fluogesterone acetate is 40-60 μm.

9. The fluoprogesterone acetate vaginal sponge of any one of claims 1-3, wherein the preparation process of the fluoprogesterone acetate vaginal sponge comprises the steps of drug solution preparation and filling.

10. The fluogesterone acetate vaginal sponge of claim 9, wherein,

the liquid medicine preparation steps are as follows:

adding a proper amount of water with the temperature of 60 ℃ into a mixing tank, keeping the water bath heating, adding hydroxypropyl methylcellulose K100m with the formula amount, and uniformly stirring; adding polyethylene glycol-4000 in the amount of the prescription, and uniformly stirring; adding the formulated amount of fluoprogesterone acetate, methyl paraben and propyl paraben, and stirring to uniformly suspend the mixture; adding the rest water with the temperature of 30 ℃; continuously stirring until the liquid medicine is stably recovered to the room temperature; detecting the viscosity of the liquid medicine to be 350-450 cps;

the filling steps are as follows:

transferring the buffer tank to a vaginal sponge filling room, and adjusting the filling amount of a filling machine to be 1.95-2.05 ml; and taking out the cleaned and dried sponges, placing the sponges on a filling line, filling and adding chemicals to each sponge, immediately transferring the filled sponges to a product drying room, and drying the sponges to constant weight by air blowing at a drying temperature of 80 +/-5 ℃.

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