CN113491672B

CN113491672B - A dripping pill containing bilobalide as effective component and its preparation method

Info

Publication number: CN113491672B
Application number: CN202010263547.6A
Authority: CN
Inventors: 孙毅; 杨勇; 李文杰; 田倩
Original assignee: Chengdu Baiyu Pharmaceutical Co Ltd
Current assignee: Chengdu Baiyu Pharmaceutical Co Ltd
Priority date: 2020-04-07
Filing date: 2020-04-07
Publication date: 2022-11-29
Anticipated expiration: 2040-04-07
Also published as: CN113491672A

Abstract

The invention provides a dripping pill with effective components containing bilobalide, which also comprises polyethylene glycol and span. The dripping pill containing the ginkgolide as the active ingredient has high preparation efficiency, can quickly achieve good mixing uniformity in the preparation process, and has good content uniformity and appearance quality.

Description

A dripping pill containing bilobalide as effective component and its preparation method

Technical Field

The invention relates to the field of pharmaceutical preparations, in particular to a dripping pill containing bilobalide as an active ingredient and a preparation method thereof.

Background

Cardiovascular and cerebrovascular diseases are diseases which are extremely harmful to human beings, and mainly comprise hypertension, coronary heart disease, stroke and the like. The diseases have the characteristics of high disease probability, high disease disability rate, high disease fatality rate and high recurrence rate. The middle aged and the elderly people over 50 years old are the high-incidence people of the diseases.

The ginkgo leaf extract is a botanical drug which is widely applied internationally and is mainly used for treating and preventing cardiovascular and cerebrovascular diseases and metabolic diseases. The main active ingredients of the ginkgo leaf extract are flavonoid compounds and ginkgolide compounds. The ginkgolides have a remarkable antagonistic effect on Platelet Activating Factor (PAF), are currently considered to be PAF factor antagonists with the most clinical application prospect, and comprise ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide J, ginkgolide M, ginkgolide K, bilobalide and the like. Pharmacological research shows that the bilobalide component has antioxidant, free radical resisting and nerve protecting effects, and has obvious curative effect on cardiac and cerebral vascular diseases.

The existing bilobalide preparation is mainly injection preparation and tablet, and in recent years, bilobalide dripping pill preparation is also appeared on the market. The dripping pill preparation has the advantages of small volume, convenient carrying, oral administration, sublingual buccal administration, high patient compliance and the like, and is favored by the market. However, the ginkgolides are difficult to dissolve, and the preparation process usually requires long stirring time, slow dissolving and dispersing speed and long defoaming time; the added dripping pills have the characteristics of small volume of single particles and light weight, and the finished product is easy to have the problems of poor content uniformity, low roundness and low percent of pass.

In order to exploit the advantages of the dripping pills, develop the market of the ginkgolide dripping pills, and research and prepare the ginkgolide dripping pills with high content uniformity, good roundness and high production efficiency, which are problems to be solved urgently.

Disclosure of Invention

The invention aims to solve the problems of long stirring time, slow dissolving and dispersing time, long defoaming time and low production efficiency in the process of preparing the ginkgolide dropping pills in the prior art; the finished product also has the technical problems of poor content uniformity, low roundness and low percent of pass, and provides the dripping pill containing bilobalide as the effective component.

A dripping pill containing bilobalide as active component is prepared from bilobalide 1-20 weight portions, polyethanediol 1-50 weight portions, and span 0.1-10 weight portions.

The ginkgolide can be in the form of a ginkgo leaf extract, and can also be a high-purity monomer compound or a composition thereof.

Preferably, the polyethylene glycol is selected from one or two or more of polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 800, polyethylene glycol 1000, polyethylene glycol 1500, polyethylene glycol 2000, polyethylene glycol 3000, polyethylene glycol 4000 and polyethylene glycol 6000; the span is sorbitan fatty acid ester; the span is selected from one or two or more of span 80 and span 85.

Preferably, the dripping pill consists of 5 to 15 parts of ginkgolide, 20 to 40 parts of polyethylene glycol and 0.5 to 5 parts of span by weight.

Preferably, the dripping pill consists of 5 to 13 parts of bilobalide, 25 to 40 parts of polyethylene glycol and 1 to 5 parts of span by weight; preferably, the composition consists of 10 to 13 parts of ginkgolide, 25 to 35 parts of polyethylene glycol and 1 to 4.5 parts of span; more preferably, the composition consists of 13 parts of ginkgolide, 35 parts of polyethylene glycol and 4.5 parts of span.

Preferably, the polyethylene glycol comprises one or two of polyethylene glycol 4000 and polyethylene glycol 6000, preferably, the polyethylene glycol consists of polyethylene glycol 400 and polyethylene glycol 4000, and more preferably, the polyethylene glycol consists of polyethylene glycol 400 and polyethylene glycol 6000.

Preferably, the span is selected from one or both of span 80 or span 85.

Preferably, the dropping pill also contains 5 to 10 parts by weight of polyethylene glycol 400.

Preferably, the ratio of the weight of the polyethylene glycol 400 to the total weight of the other polyethylene glycols except the polyethylene glycol 400 in the dripping pill is 1.

Preferably, the dripping pill consists of 10 parts of ginkgolide, 5363 parts of polyethylene glycol 400025 parts, 801 parts of span and 40010 parts of polyethylene glycol; preferably, the composition comprises 13 parts of bilobalide, 4736 parts of polyethylene glycol 600035 parts, 8978 parts of span, 854.5 parts and 4005 parts of polyethylene glycol; more preferably, the composition comprises 5 parts of bilobalide, 5363 parts of polyethylene glycol 600020 parts, 855 parts of span and 4009 parts of polyethylene glycol.

The present invention also provides a method for preparing an active ingredient comprising bilobalide, the method comprising the steps of:

s1, sieving the bilobalide and auxiliary materials;

s2, heating polyethylene glycol to be molten, adding the bilobalide prepared in the S1 and other components while stirring, uniformly stirring, and standing for defoaming;

and S3, after defoaming, dripping 30-60 drops of the whole mixture by a dripper every minute, and cooling and forming the condensate.

Preferably, the ginkgolides in the S1 pass through a 60-mesh sieve, and the auxiliary materials pass through a 80-mesh sieve; preferably, the stirring time in the S2 is 2 hours; preferably, 50 to 60 drops are made in S3 per minute.

Advantageous effects

(1) Because the ginkgolide dripping pill belongs to a low-dose medicament, the weight ratio of the ginkgolide to the used matrix auxiliary materials is 1:3-10 generally, and the water solubility of the ginkgolide is extremely poor, the ginkgolide is required to be stirred in a molten matrix for 4-7 hours in the prior art in the process of preparing the ginkgolide dripping pill so as to be dissolved and uniformly dispersed in the matrix. The ginkgolide dripping pill provided by the invention can achieve good mixing uniformity within about 2 hours of stirring especially when the ginkgolide dripping pill consists of 5-15 parts by weight of ginkgolide, 20-40 parts by weight of polyethylene glycol and 0.5-5 parts by weight of span, and the mixing uniformity (RSD) can be less than 2% within 2 hours of stirring, so that the stirring time is greatly shortened, and the production efficiency is improved. Especially when polyethylene glycol 400 is added into the prescription, the mixing uniformity can reach below 1.3%.

(2) In the process of preparing the dripping pill, in order to reach the uniformity meeting the quality standard, the prior art needs to stir for a long time, so that a large amount of foam is generated due to stirring, and the stirring usually needs to be kept stand for 3 hours or even longer for complete defoaming, but the invention adopts a scientific and reasonable formula, so that the defoaming time can be obviously shortened, and particularly when the dripping pill consists of 5-15 parts by weight of ginkgolide, 20-40 parts by weight of polyethylene glycol and 0.5-5 parts by weight of span, the defoaming time is shortened to 0.7-1 hour, so that the preparation efficiency is greatly improved. Especially, when polyethylene glycol 400 is added into the prescription, the defoaming time can reach 0.5h.

(3) The ginkgolide dripping pill prepared by the invention has good mixing uniformity, and the prepared finished dripping pill has good content uniformity, and particularly when the dripping pill consists of 5-15 parts of ginkgolide, 20-40 parts of polyethylene glycol and 0.5-5 parts of span by weight, the RSD value of the content uniformity of the finished dripping pill can reach below 2%; especially when polyethylene glycol 400 is added in the prescription, the uniformity of the finished product can reach below 1.3 percent.

(4) In order to ensure that the dropping pill has good appearance quality, such as good hardness and roundness, the dropping rate of the dropping pill is below 30d/min and the efficiency is low in the prior art, but when the dropping pill provided by the invention further comprises polyethylene glycol 400, the dropping pill can also achieve the roundness of the dropping pill of 5 minutes, the hardness of 25kN and the tailing condition of the dropping pill of 9-10 minutes under the condition that the dropping rate is 60d/min, and the appearance quality is excellent.

Detailed Description

Unless otherwise indicated, the raw materials and equipment described in the mode of the specific test examples of the present invention are known and commercially available products.

The ginkgolide can be a ginkgo leaf extract, and also can be a monomeric compound with high purity or a composition thereof.

The ginkgolide can be obtained by separation and purification in the prior art, and further can be obtained by a solvent extraction method, a column extraction method, a solvent extraction-column extraction method, a supercritical extraction method, a chromatography or column chromatography purification method and the like.

Preferably, the ginkgolides of the invention are obtained by the method disclosed in WO 2013159412A 1.

The ginkgolides of the present invention may also be obtained in a commercially available manner.

The invention relates to a preparation method of a dripping pill containing bilobalide as an active ingredient, wherein condensed liquid can be aqueous condensate, such as water, ethanol with different concentrations and the like, or oily condensate, such as liquid paraffin, simethicone, vegetable oil, gasoline or a mixture thereof and the like.

1. Research on influence of different formulas on uniformity of ginkgolide dropping pills

1. Preparing the dripping pills to be tested

The bilobalide dripping pill is prepared in the following weight proportion of 1 to 12.

The preparation method comprises the following steps:

the following preparation methods are adopted for the formulas 1 to 4 and the formulas 6 to 16:

s1, sieving the raw materials with a 60-mesh sieve, and sieving other auxiliary materials with a 80-mesh sieve;

s2, heating the substrate to be molten; adding the raw materials and other additive materials during stirring; stirring for 4 hours; standing for defoaming;

and S3, after defoaming, dripping 30 drops of the whole mixture by a dripper per minute, cooling and forming in liquid paraffin at 15 ℃, wiping off condensate adhered to the surface, and preparing 5 ten thousand dropping pills.

The following preparation method is adopted in the formula 5:

s1, sieving the ginkgolide with a 60-mesh sieve; dissolving the sieved bilobalide in ethanol;

s2, heating polyethylene glycol to be molten; adding the ginkgolide ethanol dispersion solution while stirring, and stirring for 4 hours; standing for defoaming;

and S3, after defoaming, dripping 30 drops of the whole mixture by a dripper per minute, cooling and forming in liquid paraffin at 15 ℃, wiping off condensate adhered to the surface, and preparing 5 million pills.

2. Determination of mixing uniformity of dripping pill preparation

The determination method comprises the following steps: in the stirring process of the dripping pill materials in the formulas 1-16, respectively taking 2g of dripping pill preparation liquid at the upper layer edge, the upper layer middle part, the middle layer edge, the middle layer middle part, the bottom layer edge and the bottom layer middle part of the solution respectively at the stirring time of 30min, the stirring time of 60min, the stirring time of 90min, the stirring time of 120min, the stirring time of 180min, the stirring time of 210min and the stirring time of 240min, measuring the content of the total ginkgolides at 6 points by an HPLC method, calculating a standard deviation SD value, calculating a relative standard deviation RSD of a sample according to the SD value, wherein the calculation method of the RSD is shown in a formula 1 (the same below), and counting the calculation results of the RSD to a table 1.

Formula 1 relative standard deviation calculation formula

3. Statistics of defoaming duration of dropping pills

The statistical method comprises the following steps: counting the time required for the dropping pills of the formulas 1 to 16 to naturally defoam when the stirring of the dropping pills of the formulas 1 to 16 is stopped and the timing is stopped when the foam of the dropping pill solution dissipates, wherein the results are shown in table 2.

4. Evaluation of appearance quality of dropping pill

The evaluation method comprises the following steps: evaluating the appearance quality of the dripping pills with the formulas 1 to 16, wherein the evaluation items comprise: hardness (KN), pill roundness, pill tailing (scored from 0 to 10, with 10 being the best and 0 being the worst), and the results are shown in table 3;

the measuring method of the roundness of the dripping pill comprises the following steps: expressed by the shortest diameter/longest diameter of the dripping pill, the ratio is more than 0.95 and is 5 minutes, between 0.9 and 0.95 and is 4 minutes, between 0.85 and 0.9 and is 3 minutes, between 0.8 and 0.85 and is 2 minutes, and below 0.8 and is 1 minute.

5. Determination of content uniformity of dripping pills

The determination method comprises the following steps: taking 20 pills of each formula as 1 part of the pill sample, sampling 10 parts in total, respectively measuring the content of the ginkgolides in each pill, calculating the relative standard deviation RSD value, and counting the RSD calculation results to table 4.

6. Results and analysis

TABLE 1 mixing uniformity (RSD) of drop pill preparation

TABLE 2 duration of drop pill defoaming

TABLE 3 evaluation of appearance quality of dropping pills

TABLE 4 content uniformity of finished dripping pills (RSD)

The existing bilobalide dripping pills have the problems of poor content uniformity, long production time consumption and low efficiency, and in order to solve the problems, the inventor tries to adjust the matrix and auxiliary materials used by the dripping pills so as to obtain the dripping pills with uniform texture and high production efficiency.

Polyethylene glycol, glycerol and the like are common substrates of the dropping pills, the inventor firstly prepares three types of dropping pills by using ginkgo biloba extract, ginkgo biloba extract and ginkgolide as effective components respectively through a formula 1 to a formula 4, uses PEG6000 and glycerol as substrates and does not use other additives, researches the mixing uniformity and the content uniformity after condensation and pill formation of the three types of dropping pills under the state of solution, and can know that the uniformity and the content uniformity of the three types of dropping pills are poor according to tables 1 to 4.

Thus, the inventor tries to add solubilizer (formula 5, formula 6) into polyethylene glycol matrix, and change the matrix and solubilizer (formula 7-formula 9) in order to improve the dissolution and dispersion efficiency of the dripping pill, and as can be seen from table 1-table 4, the dripping pills of formula 5-formula 8 have slightly improved but not good effect, but when span 20 is used as additive and glycerin is used as matrix in formula 9, the effects of the mixing uniformity of the dripping pill preparation and the content uniformity of the dripping pills are greatly improved, the uniformity of the preparation can reach 4.9% in 240min, the content uniformity of the finished dripping pills can reach 4.56%, and the dissolution and dispersion efficiency is superior to that of other formulas.

Combining the test results of formulas 3-9, the inventor selects PEG4000 and PEG6000 as the matrix, further studies the effect of the bilobalide dropping pill prepared by compounding span 20, span 40, span 80, span 85 and the solubilizer (formula 10-formula 13), and finds that the span-based solubilizer has different improvement effects, but unexpectedly, the dropping pill prepared from span 80, span 85, PEG4000 and PEG6000 has remarkably better uniformity than other span formulas, and the beneficial effect can be weakened by combining span and other solubilizers (formula 14), so that the dropping pill effect is poor. As can be seen from Table 1, after the dripping pill is stirred for 120min, the mixing uniformity is kept below 2% to complete dissolution, and all layers of the solution are uniform; according to tables 2-3, the defoaming time of the dropping pills prepared by using span 80 and span 85 is shortened to be within 1 hour from 3.1 hours, the preparation efficiency of the dropping pills is greatly improved, the appearance quality of the dropping pills is improved, and meanwhile, according to table 4, the content uniformity of finished dropping pills can be within 2 percent, and the effect is extremely excellent.

Experimental example 2 influence of different ratios on uniformity and quality difference of ginkgolide dripping pills

1. Preparing ginkgolide dripping pills with different proportions

The bilobalide dripping pill is named as formula 17-formula 25 according to the following proportion.

The preparation method comprises the following steps:

the following preparation methods are adopted for the formulas 17 to 25:

s1, sieving the ginkgolides with a 60-mesh sieve, and sieving other auxiliary materials with a 80-mesh sieve;

s2, heating polyethylene glycol to be molten, adding bilobalide and other auxiliary materials while stirring, stirring for 2 hours, standing and defoaming;

and S3, after defoaming, dripping all the mixture by using a dripper, cooling and forming in liquid paraffin at 15 ℃, wiping off condensate adhered to the surface, and preparing 5 ten thousand dripping pills.

Wherein, 30 pills are prepared per minute in the bilobalide pill S3 according to the formula 17-20, 50 pills are prepared per minute in the bilobalide pill S3 according to the formula 21-22, and 60 pills are prepared per minute in the bilobalide pill S3 according to the formula 23-25.

2. Determination of mixing uniformity of dripping pill preparation

The determination method comprises the following steps: in the stirring process of the dripping pill materials of the formulas 17-25, respectively taking 2g of dripping pill preparation liquid at the upper layer edge, the upper layer middle part, the middle layer edge, the middle layer middle part, the bottom layer edge and the bottom layer middle part of the solution after stirring for 30min, 60min, 90min and 120min, measuring the content of the total ginkgolides at 6 points by an HPLC method, calculating the relative standard deviation RSD of a sample, and counting the calculation result of the RSD to the table 5.

3. Statistics of defoaming duration of dropping pills

The statistical method comprises the following steps: counting the time required for the natural defoaming of the dripping pills of the formulas 17 to 25 when the stirring of the dripping pills of the formulas 17 to 25 is stopped and the time required for the natural defoaming of the dripping pills of the formulas 17 to 25 is stopped when the foam of the dripping pill solution is dissipated, wherein the results are shown in table 6.

4. Evaluation of appearance quality of dropping pill

The evaluation method comprises the following steps: evaluating the appearance quality of the dripping pills with the formula 17-25, wherein the evaluation items comprise: hardness (KN), pill roundness, pill tailing (scored from 0 to 10, with 10 being the best and 0 being the worst), and the results are shown in table 7;

5. Determination of content uniformity of dripping pills

The determination method comprises the following steps: taking 20 pills of each formula as 1 part of pill sample, sampling 10 parts in total, respectively measuring the relative content of each single dosage, calculating the relative standard deviation RSD value, and counting the RSD calculation result to table 8.

7. Results and analysis

TABLE 5 mixing uniformity of the drop pill preparation

TABLE 6 duration of drop pill defoaming

TABLE 7 evaluation of appearance quality of dropping pills

TABLE 8 content uniformity of dropping pills RSD value

Item	Content uniformity
		Formulation 17	3.95％
Formulation 18	3.39％
		Formulation 19	1.91％
Formulation 20	1.98％
		Formulation 21	1.65％
Formulation 22	1.56％
		Formulation 23	1.27％
Formulation 24	1.21％
		Formulation 25	1.01％

Through the research of experimental example 1 on ginkgolide dropping pills with different formulas, the inventor finds that the ginkgolide dropping pills prepared by using ginkgolide, polyethylene glycol 4000 or polyethylene glycol 6000, span 80 or span 85 can have better mixing uniformity and content uniformity and shorter defoaming time than other formulas, but the appearance quality of the dropping pills is not excellent enough, and the roundness, hardness and tailing condition of the dropping pills can be further improved; therefore, the inventors have adjusted the ratio of the ginkgolide dripping pills and studied the ginkgolide dripping pills with different ratios to find the ginkgolide dripping pills with more excellent effect.

According to tables 5-8, when the dripping pill contains 5-15 parts of ginkgolide, 20-40 parts of polyethylene glycol 4000 or polyethylene glycol 6000, and 20-5 parts of span 80 or span 850.5 (formula 19-formula 22), the mixing uniformity of the dripping pill preparation solution can reach 1.5-1.9% after the dripping pill preparation solution is stirred for 2 hours; the defoaming time of the dripping pills can be shortened to 0.7-1 hour; the content uniformity of the finished dripping pills can reach 1.56-1.98%.

Although the dropping pills prepared by the formulations 19 to 22 have been able to achieve good mixing uniformity, content uniformity and shorter defoaming time, the inventors considered that optimization of the efficiency of the dropping pill preparation could also be attempted; the inventors then conducted further studies.

Firstly, the inventors compare the appearance quality of the dripping pills of formula 12-formula 13 and formula 19-formula 20 through the evaluation test of the appearance quality of the dripping pills (table 3 and table 7), and find that the dripping pills can obtain the scores of 3-4 minutes of roundness, 22-25KN of hardness and 7-9 minutes of tailing condition at the dripping speed of 30 d/min; then, the inventor tries to accelerate the dropping speed, in the formula 21-22, the inventor modifies the dropping speed of the dropping pill to 50d/min, and as a result, the roundness, hardness and tailing condition of the dropping pill tend to be worsened, and in order to solve the problem, the inventor further optimizes the formula, and finally finds that the roundness, hardness and tailing condition of the dropping pill can be greatly improved by adding PEG400 into the matrix for compounding through a plurality of tests and screens, even under the condition that the dropping speed of the dropping pill is 60d/min, the roundness of the dropping pill can be 5 minutes, the hardness is 25kN, and the tailing condition of the dropping pill is 9-10 minutes; the invention surprisingly shortens the defoaming time of the dropping pill to be within 0.5 hour after adding the PEG400, optimizes the mixing uniformity and the content uniformity, and can reach 1.0 to 1.2 percent; the uniformity of finished dripping pills can reach 1.01 to 1.27 percent, and the dripping pills have excellent effect.

In conclusion, the invention provides a ginkgolide dripping pill preparation and a preparation method thereof, wherein the preparation has excellent uniformity and appearance quality, and the preparation efficiency of the dripping pill can be improved to 60d/min.

The foregoing is illustrative of the preferred embodiments of the present invention and is not to be construed as limiting thereof, since modifications may be made to the embodiments and their application within the scope of the appended claims.

Claims

1. A dripping pill containing bilobalide as effective component is characterized in that the dripping pill is composed of 5-15 parts of bilobalide, 20-40 parts of polyethylene glycol and 0.5-5 parts of span;

the polyethylene glycol comprises polyethylene glycol 400 and also comprises one or two of polyethylene glycol 4000 or polyethylene glycol 6000; the ratio of the weight of the polyethylene glycol 400 to the total weight of other polyethylene glycols except the polyethylene glycol 400 in the dripping pill is 1;

the span is selected from one or two of span 80 and span 85.

2. The dripping pill according to claim 1, wherein the dripping pill comprises 5-13 parts by weight of bilobalide, 25-40 parts by weight of polyethylene glycol and 1-5 parts by weight of span.

3. The dripping pill according to claim 2, wherein the dripping pill comprises 10-13 parts by weight of ginkgolide, 25-35 parts by weight of polyethylene glycol and 1-4.5 parts by weight of span.

4. The dripping pill according to claim 2, wherein the dripping pill comprises 13 parts by weight of ginkgolide, 35 parts by weight of polyethylene glycol and 4.5 parts by weight of span.

5. The dripping pill according to claim 1, wherein the polyethylene glycol consists of polyethylene glycol 400 and polyethylene glycol 4000.

6. The dripping pill according to claim 1, wherein the polyethylene glycol consists of polyethylene glycol 400 and polyethylene glycol 6000.

7. The dripping pill according to claim 1, wherein the dripping pill comprises at least 400 to 10 parts by weight of polyethylene glycol.

8. The dripping pill according to claim 1, wherein the dripping pill comprises 10 parts by weight of bilobalide, 4000 parts by weight of polyethylene glycol, 80 parts by weight of span and 10 parts by weight of polyethylene glycol.

9. The dripping pill according to claim 1, wherein the dripping pill comprises 13 parts by weight of bilobalide, 6000 parts by weight of polyethylene glycol, 85.5 parts by weight of span and 400 parts by weight of polyethylene glycol.

10. The dripping pill according to claim 1, wherein the dripping pill comprises 5 parts by weight of bilobalide, 6000 parts by weight of polyethylene glycol, 85 parts by weight of span and 400 parts by weight of polyethylene glycol.

11. Method for the preparation of the dripping pill according to any of claims 1 to 10, comprising the steps of: s1, sieving the bilobalide and auxiliary materials; s2, heating polyethylene glycol to be molten, stirring and adding the bilobalide and other components prepared in the step S1, uniformly stirring, standing and defoaming; and S3, after defoaming, dripping 30-60 drops of the whole mixture by a dripper every minute, and cooling and forming the condensate.

12. The method according to claim 11, wherein the bilobalide in S1 is sieved with a 60 mesh sieve, and the adjuvant is sieved with a 80 mesh sieve.

13. The method according to claim 12, wherein the stirring time in S2 is 2 hours.

14. The preparation method of claim 12, wherein the drop pills in S3 are prepared into 50-60 drops per minute.