Lcidipine film-controlled sustained-release pellet capsule and preparation method thereof

Abstract

The invention discloses a lacidipine film-controlled sustained-release pellet capsule and a preparation method thereof, relates to the technical field of medicines, and aims to solve the problem of release reduction caused by film aging of a lacidipine film-controlled sustained-release pellet prepared by an aqueous dispersion coating. The preparation method comprises the following steps: respectively weighing a lacidipine bulk drug, a polymer carrier material and a plasticizer according to a prescription amount, grinding and uniformly mixing to prepare the lacidipine solid dispersion. A sustained-release coating film of the pellet capsule contains Eurdragit RL30D, a plasticizer triethyl citrate and an anti-sticking agent talcum powder, and a pellet core contains croscarmellose sodium and an excipient. According to the lacidipine solid dispersion solid preparation provided by the invention, lacidipine exists in the carrier material in a microcrystalline state, an amorphous state, a colloidal dispersion state or a molecular dispersion state, so that the lacidipine solid dispersion solid preparation has high dispersity, the dissolution speed of a medicine is accelerated, the absorption of the medicine can be promoted, and the bioavailability is improved.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines, and particularly relates to a lacidipine capsule and a preparation method thereof. Background Art

[0002] Lacidipine is a third-generation calcium antagonist. Its chemical name is: (E)-4-[2-[3-(carboxy-tert-butyl)-3-oxo-1-propenyl]phenyl]-1,4-dihydro-2,6-dimethyl-3,5-pyridine-dicarboxylic acid diethyl ester. Molecular formula: C 26 H 33 N06, molecular weight: 455.59, structural formula is as follows:

[0003]

[0004] Lacidipine, as a new type of dihydropyridine calcium ion antagonist, has strong vascular selectivity, diuretic and antioxidant effects, and has no significant effect on the cardiac conduction system and myocardial contractile function. It is reported that lacidipine taken orally once a day at a dose of 2-6 mg can reduce SBP and DBP in hypertensive patients within 24 hours. When used alone, it has similar antihypertensive effects as other calcium ion antagonists, beta blockers and ACEI preparations, and has no significant effect on heart rate, blood sugar, blood lipids, etc. The therapeutic effect is even better than other antihypertensive drugs, and it is well tolerated. Basic research has shown that it has stronger vascular selectivity than nifedipine, nitrendipine, verapamil and amlodipine, and is also highly selective for the inhibitory effect on vasoconstriction caused by potassium ion depolarization. Extracellular calcium ions through calcium ion control channels can increase this inhibitory effect, while its negative inotropic effect on the heart is relatively weak. This high selectivity of lacidipine for blood vessels helps explain its strong antihypertensive effect. The ideal antihypertensive drug is to keep blood pressure stably controlled for 24 hours to prevent damage to target organs caused by blood pressure fluctuations. Lacidipine is a long-acting preparation that fully meets the above requirements.

[0005] In order to improve the solubility of lacidipine, patent CN1839835A dissolves lacidipine and polyvinyl pyrrolidone in organic solvents such as acetone and ethanol, and uses the solution as an adhesive to prepare a soft material, thereby achieving the purpose of improving the solubility of lacidipine. However, this method uses a large amount of organic solvents, which may lead to the problem of residual organic solvents, and the content of the prepared tablets is uneven. In addition, patent CN104000790A attempts to use a micronization technology to improve the solubility of lacidipine, but this method is very limited in improving the solubility of lacidipine when no solubilizer is added, and the solubility can only reach 10.77%, which cannot meet its dissolution requirements under non-sink conditions (greater than 30%). Patent CN102198107 uses a supercritical method to prepare lacidipine silica gel adsorption solid dispersion to improve its solubility, but long-term oral administration of preparations containing silicon may cause safety problems. In addition, CN102008471A adopts self-microemulsification method to prepare microemulsion to improve lacidipine dissolution, but there are cumbersome operation, complex process, and the shortcomings of excessive surfactant dosage. Amorphous solid dispersion has become one of the effective methods to improve the dissolution of poorly soluble drugs in recent years. Poorly soluble drugs are prepared into solid dispersions using highly water-soluble carrier materials, improve drug solubility, and accelerate the drug dissolution rate with outstanding effects, and obtain increasingly widespread attention and application. Traditional solid dispersion preparation methods have: melting method, solvent method, grinding method, spray drying method, but due to the problems of complex process, low reproducibility, organic solvent residue in these preparation methods, industrial promotion difficulty is relatively large. Hot melt extrusion is a new solid dispersion technology for preparing applied to the field of pharmaceutical preparations in recent years, and it adds bulk drug and polymer auxiliary materials to extruder simultaneously, so that material experience solid delivery, melting, melt delivery three stages, under the strong shearing action of kneading device and screw element, highly mixed and dispersed molded products are obtained, and what is particularly valuable is that preparation technology is easy to realize industrial amplification production.

[0006] At present, the only lacidipine dosage form available in China and imported is ordinary tablets. However, lacidipine is a small-dose, extremely insoluble drug. The dissolution rate of lacidipine tablets prepared by traditional production processes is slow, and they slowly disintegrate and dissolve in the body, which is prone to solubility problems, making the drug slow to take effect in the body and reducing its effect, thereby affecting the absorption of the drug in the body; at the same time, most hypertensive patients are elderly people, and it is difficult for them to swallow ordinary tablets. Therefore, it is also necessary to develop lacidipine preparations and preparation methods with short disintegration time, rapid drug dissolution and stable efficacy.

[0007] Micropills are a type of dispersed dosage form with a dose, which is more evenly dispersed in the body, has a larger contact area with tissue mucosa, takes effect faster, has higher bioavailability, is less irritating, and can also reduce individual absorption differences. Lacidipine is contained therein with good sealing, which is more conducive to improving the stability of lacidipine during the process and storage. Sustained-release micropills are a multi-unit sustained-release drug release system made of drugs, which are generally taken orally after being loaded into capsules. After the capsules are dissolved, the sustained-release micropills can be widely and evenly distributed in the gastrointestinal tract. The most commonly used method for implementing sustained-release micropills is to use membrane-controlled type. In the early years, organic solvents were mostly used to prepare the coating liquid of the sustained-release coating film. Due to the pollution and safety problems of the organic solvent coating liquid, in order to overcome the defects of the organic solvent coating liquid, the aqueous dispersion coating technology has been widely used. However, it was found that the membrane-controlled sustained-release micropill capsules prepared by aqueous dispersion coating had good release performance within a period of time just after preparation, but after storage for a period of time, their release performance began to decline, and the longer the storage time, the more obvious the decline. Analysis shows that the reason is that during the storage process, the coating membrane becomes gradually tighter due to the continuous combination of water dispersion particles, which causes the membrane permeability to decrease and the release to slow down, which is commonly known as aging. Summary of the invention

[0008] The purpose of the present invention is to solve the problem of decreased release caused by membrane aging of lacidipine membrane-controlled sustained-release micropellets prepared by water dispersion coating, and to provide a membrane-controlled lacidipine sustained-release micropellet capsule that can always maintain stable release performance during the validity period. The micropellet core contains cross-linked sodium carboxymethyl cellulose with high water swelling properties, and the sustained-release coating film is deformed by swelling due to water absorption, thereby offsetting the aging of the film.

[0009] A method for preparing a lacidipine solid dispersion of the present invention comprises:

[0010] The next step is: weighing the prescribed amount of lacidipine raw material, polymer carrier material and plasticizer respectively, grinding and mixing to prepare lacidipine solid dispersion.

[0011] Furthermore, the solid dispersion is prepared from the following components in weight percentage: 16-18% of lacidipine, 74-76% of polymer carrier material, and 8-9% of plasticizer.

[0012] Furthermore, the plasticizer is Span 20, and the polymer carrier material is hydroxypropylmethylcellulose acetate succinate.

[0013] Furthermore, the preparation method is a hot melt extrusion method, and the specific steps are as follows: weigh the prescribed amount of lacidi

[0014] The flat, carrier material and plasticizer are mixed and added into a twin-screw hot melt extruder, and extruded at a temperature of 100°C to 130°C and a speed of 20rpm / min. After the extrudate is cooled, it is crushed and passed through an 80-mesh sieve to obtain the solid dispersion.

[0015] The present invention discloses a lacidipine membrane-controlled sustained-release micro-pellet capsule, which contains the lacidipine solid dispersion of the present invention; wherein the sustained-release coating of the micro-pellet capsule comprises Eurdragit RL30D, a plasticizer triethyl citrate and an anti-adhesive talc, and the pellet core comprises cross-linked sodium carboxymethyl cellulose and an excipient.

[0016] Furthermore, the excipient is a filler such as microcrystalline cellulose, lactose or a solubilizer such as sodium lauryl sulfate.

[0017] Furthermore, the percentage of cross-linked sodium carboxymethyl cellulose in the pellet core of the micro-pellet capsule is 5-15% by weight.

[0018] Furthermore, the weight ratio of Eurdragit RL 30D: triethyl citrate: talc is 10:1:1-2.

[0019] The coating weight gain is 13% to 30%.

[0020] The lacidipine membrane-controlled sustained-release micropill capsule of the present invention has the following prescription based on 1000 capsules:

[0021]

[0022] Compared with the prior art, the characteristics and beneficial effects of the present invention are:

[0023] 1. The lacidipine solid dispersion solid preparation provided by the present invention, in which lacidipine exists in a carrier material in a microcrystalline state, an amorphous state, a colloid dispersion state or a molecular dispersion state, has a large dispersion degree, accelerates the dissolution rate of the drug, can promote the absorption of the drug, and improves the bioavailability.

[0024] 2. The polymer carrier material used in the present invention is hydroxypropylmethylcellulose acetate succinate (HPMCAS). During the hot melt extrusion process, the appropriate carrier concentration, viscosity and substituents will not only affect the release of the drug, but also effectively prevent the drug from "recrystallizing", thereby increasing its stability. The hydroxypropylmethylcellulose succinate (HPMCAS) carrier used in the present invention has an excellent crystallization inhibition effect, which solves the problem of product precipitation after dissolution of the solid dispersion prepared by using carrier materials such as copolyvidone, and the prepared solid dispersion has relatively low hygroscopicity and high stability.

[0025] 3. Existing lacidipine is limited to tablets and dispersible tablets, which belong to capsules, and lacidipine is a water-insoluble API. The first step is to increase solubility using solid dispersion technology. Because hypertensive patients need a more stable blood pressure level, the present invention adopts sustained-release micropill coating technology, and the sustained-release micropill can be widely and evenly distributed in the gastrointestinal tract, so that it can exert its pharmacological effect more steadily and evenly, achieving the effect of stabilizing blood pressure.

[0026] 4. The micropills of the present invention use a pellet core containing highly swellable cross-linked sodium carboxymethyl cellulose. Since cross-linked sodium carboxymethyl cellulose is insoluble in water, but can absorb water several times its own weight and swell, the volume of the micropills becomes larger, resulting in the sustained-release membrane being stretched, the thickness becoming thinner, the pore size of the water-permeable micropores becoming larger, and the permeability becoming better, which can compensate for the decrease in permeability caused by membrane aging, thereby making the release rate in the middle and late stages basically constant. In addition, it can also avoid changes in release performance caused by membrane relaxation in the future, so that the drug release rate is basically constant throughout the effective period. This can greatly improve the anti-aging performance of the lacidipine membrane-controlled sustained-release micropills coated with water dispersions.

[0027] 5. The plasticizer Span20 used in the present invention can effectively reduce the co-extrusion temperature of lacidipine drug and carrier material while ensuring rapid dissolution of solid dispersion and significantly improving bioavailability, thereby improving the stability of solid dispersion and reducing production cost and energy consumption.

[0028] 6. The main purpose of the present invention is to provide a lacidipine film-controlled sustained-release micropellet capsule, wherein the sustained-release coating of the micropellet adopts Eurdragit RL 30D as the film-forming material, and the core of the micropellet contains highly swellable cross-linked sodium carboxymethyl cellulose and other pharmaceutically acceptable excipients for sustained-release micropellets. DETAILED DESCRIPTION

[0029] In order to make the objectives, technical solutions and advantages of the embodiments of the present invention more clearly understood, the spirit of the contents disclosed by the present invention will be described in detail below. After understanding the embodiments of the contents of the present invention, any technician in the relevant technical field can change and modify them according to the techniques taught by the contents of the present invention without departing from the spirit and scope of the contents of the present invention.

[0030] The exemplary embodiments of the present invention and the description thereof are used to explain the present invention but are not intended to limit the present invention.

[0031] Example 1 Lacidipine sustained-release pellet capsules with common pellet core

[0032] prescription

[0033] 1. Lacidipine solid dispersion prescription (1000g)

[0034] Lacidipine 16.7%

[0035] Polymer carrier material 75%

[0036] Plasticizer 8.3%

[0037] (1) The raw material lacidipine and the pharmaceutical excipients are crushed and passed through a 60-100 mesh sieve respectively, and mixed uniformly according to a certain proportion to form a physical mixture; the pharmaceutical excipients are the above-mentioned polymer carrier material and plasticizer;

[0038] (2) The temperature of the twin-screw hot-melt extruder is set to 100° C. to 130° C., and the screw speed of the hot-melt extruder is set to 20 rpm / min. The physical mixture in step 1) is added to the extruder, melted, extruded, and finally extruded in a strip shape:

[0039] (3) After the strip-shaped extrudate is cooled, it is crushed and passed through an 80-mesh sieve to obtain a drug solid dispersion.

[0040] Example 1 Lacidipine sustained-release micropellet capsule prescription with common pellet core

[0041] Tablet prescription (1000 tablets)

[0042]

[0043] 2% sodium carboxymethyl cellulose 10% ethanol solution

[0044] Sustained release film coating formulation

[0045]

[0046] Preparation process

[0047] 1. Pellet core preparation process:

[0048] Weigh the prescribed amount of solid dispersion, microcrystalline cellulose PH101, lactose, and sodium lauryl sulfate, and mix them evenly in a wet granulator; prepare a soft material with 2% sodium carboxymethyl cellulose 10% ethanol solution; extrude on an extruder with a screen aperture of 1.0 mm and an extrusion speed of 20 to 30 rpm; spheronize with a spheronization speed of 900 to 1000 rpm; dry in a fluidized bed; sieve and take pellet cores with a mesh size of 16 to 30.

[0049] 2. Preparation process of sustained-release film coating solution:

[0050] Weigh the prescribed amount of triethyl citrate and put it into the prescribed amount of water, stir evenly, then add the prescribed amount of talcum powder, stir and shear evenly, and finally add Eurdragit RL30D and mix evenly to obtain the product.

[0051] 3. Coating (sustained release coating):

[0052] The pellet cores were placed in a fluidized bed for coating, and the coating weight gain was controlled to be 13.5%.

[0053] 4. Heat treatment: Heat treat the sustained-release coated pellets in a fluidized bed at 40°C / 2h.

[0054] 5. Filling capsules: Fill the coated pellets on a capsule filling machine.

[0055] Dissolution, content determination and swelling rate investigation

[0056] According to the quality standard requirements of the 2020 edition of the Chinese Pharmacopoeia, the lacidipine sustained-release micropellets were subjected to accelerated dissolution tests for 0, 1, 2, 3, and 6 months, and the stability of the above samples was investigated and tested. The results are shown in Table 1. The dissolution was determined according to the dissolution and release assay (General Rule 0931 Method 2). The content was determined according to the high-performance liquid chromatography method (General Rule 0512), and the operation was protected from light. The results are shown in Table 2. The expansion rate was tested, and the results are shown in Table 3.

[0057] Table 1 Cumulative dissolution test results and content determination results of Example 1

[0058]

[0059] Table 2 Example 1 content determination results

[0060] time Day 0 1M 2M 3M 6M content 99.0％ 97.9％ 98.0％ 91.2％ 85.9％

[0061] Table 3 Expansion rate measurement results of Example 1

[0062] time 2h 4h 8h 0M 20.3％ 38.1％ 50.1％ 1M 18.1％ 36.0％ 47.2％ 2M 15.4％ 31.9％ 44.4％ 3M 11.8％ 27.3％ 40.4％ 6M 10.5％ 23.4％ 34.2％

[0063] The results showed that the lacidipine sustained-release micropellet capsules in Example 1, whose core did not contain expandable materials, had good initial release. However, as the storage time increased, the membrane aged continuously, the release rate slowed down, and the residue increased significantly.

[0064] Example 2 Formulation of Lacidipine Sustained-Release Micropellets Capsules Containing 5% Cross-linked Carboxymethyl Cellulose Sodium

[0065] Tablet prescription (1000 tablets)

[0066]

[0067] 2% sodium carboxymethyl cellulose 10% ethanol solution

[0068] Sustained release film coating formulation

[0069]

[0070] Preparation process

[0071] 1. Pellet core preparation process:

[0072] Weigh the prescribed amount of solid dispersion, microcrystalline cellulose PH101, lactose, sodium lauryl sulfate, and cross-linked sodium carboxymethyl cellulose and mix them evenly in a wet granulator; prepare a soft material with 2% sodium carboxymethyl cellulose 10% ethanol solution; extrude on an extruder with a screen aperture of 1.0 mm and an extrusion speed of 20 to 30 rpm; spheronize with a spheronization speed of 900 to 1000 rpm; dry in a fluidized bed; sieve and take pellet cores with a mesh size of 16 to 30.

[0073] 2. Preparation process of sustained-release film coating solution:

[0074] Same as Example 1.

[0075] 3. Coating (sustained-release film): Place the pellet cores in a fluidized bed for coating, and control the weight gain of the film. The coating weight gain is 20.7%.

[0076] 4. Heat treatment: Heat treat the sustained-release coated pellets in a fluidized bed at 40°C / 2h.

[0077] 5. Filling capsules: Fill the coated pellets on a capsule filling machine.

[0078] Dissolution, content determination and results

[0079] The determination method is the same as in Example 1, and the results are shown in Tables 4, 5 and 6.

[0080] Table 4 Cumulative dissolution test results and content determination results of Example 2

[0081]

[0082] Table 5 Example 2 Assay results

[0083] time Day 0 1M 2M 3M 6M content 100.8％ 99.2％ 98.9％ 99.2％ 99.9％

[0084] Table 6 Expansion rate measurement results of Example 2

[0085] time 2h 4h 8h 0M 37.8％ 65.7％ 90.1％ 1M 38.8％ 67.4％ 89.4％ 2M 37.4％ 65.3％ 89.9％ 3M 37.8％ 68.9％ 89.7％ 6M 38.2％ 68.5％ 89.2％

[0086] The results show that the initial release performance of the lacidipine sustained-release micropellet capsules containing 5% cross-linked carboxymethyl cellulose sodium in Example 2 is good, and the release effect is still good as the storage time increases. The expansion rate remains unchanged, which offsets the aging of the sustained-release coating.

[0087] Example 3 Formulation of Lacidipine Sustained-Release Micropellets Capsules Containing 10% Cross-linked Sodium Carboxymethylcellulose

[0088] Tablet prescription (1000 tablets)

[0089]

[0090] 2% sodium carboxymethyl cellulose 10% ethanol solution

[0091] Sustained release film coating formulation

[0092]

[0093] Preparation process

[0094] 1. Pellet core preparation process:

[0095] Same as Example 2.

[0096] 2. Preparation process of sustained-release film coating solution:

[0097] Same as Example 1.

[0098] 3. Coating (sustained release coating):

[0099] The pellet cores were placed in a fluidized bed for coating, and the coating weight gain was controlled to be 25.7%.

[0100] 4. Heat treatment: Heat treat the sustained-release coated pellets in a fluidized bed at 40°C / 2h.

[0101] 5. Filling capsules: Fill the coated pellets on a capsule filling machine.

[0102] Dissolution, content determination and results

[0103] The determination method is the same as in Example 1, and the results are shown in Tables 7, 8 and 9.

[0104] Table 7 Cumulative dissolution test results and content determination results of Example 3

[0105]

[0106]

[0107] Table 8 Example 3 Assay results

[0108] time Day 0 1M 2M 3M 6M content 99.5％ 98.2％ 98.0％ 97.9％ 98.2％

[0109] Table 9 Expansion rate measurement results of Example 3

[0110] time 2h 4h 8h 0M 42.1％ 76.1％ 99.7％ 1M 42.7％ 75.8％ 98.9％ 2M 42.3％ 75.9％ 99.2％ 3M 42.7％ 76.0％ 99.5％ 6M 42.2％ 76.0％ 99.6％

[0111] The results show that the initial release performance of the lacidipine sustained-release micropellet capsules containing 10% cross-linked carboxymethyl cellulose sodium in Example 3 is good, and the release effect is still very good as the storage time increases, and the final release residue is very small. The expansion rate remains unchanged, which offsets the aging of the sustained-release film.

[0112] Example 4 Formulation of Lacidipine Sustained-Release Micropellets Capsules Containing 15% Cross-linked Sodium Carboxymethylcellulose

[0113] Tablet prescription (1000 tablets)

[0114]

[0115] 2% sodium carboxymethyl cellulose 10% ethanol solution

[0116] Sustained release film coating formulation

[0117]

[0118] Preparation process

[0119] 1. Pellet core preparation process:

[0120] Same as Example 2.

[0121] 2. Preparation process of sustained-release film coating solution:

[0122] Same as Example 1.

[0123] 3. Coating (sustained release coating):

[0124] The pellet cores were placed in a fluidized bed for coating, and the coating weight gain was controlled to be 30.4%.

[0125] 4. Heat treatment: Heat treat the sustained-release coated pellets in a fluidized bed at 40°C / 2h.

[0126] 5. Filling capsules: Fill the coated pellets on a capsule filling machine.

[0127] Dissolution, content determination and results

[0128] The determination method is the same as in Example 1, and the results are shown in Tables 10, 11 and 12.

[0129] Table 10 Cumulative dissolution test results and content determination results of Example 4

[0130]

[0131] Table 11 Example 4 Assay results

[0132] time Day 0 1M 2M 3M 6M content 99.8％ 98.9％ 98.8％ 98.2％ 99.1％

[0133] Table 12 Expansion rate measurement results of Example 4

[0134] time 2h 4h 8h 0M 44.3％ 77.1％ 102.0％ 1M 43.9％ 77.1％ 101.4％ 2M 44.4％ 78.0％ 102.1％ 3M 42.8％ 77.9％ 101.9％ 6M 43.5％ 77.2％ 101.9％

[0135] The results show that the initial release performance of the lacidipine sustained-release micropellet capsules containing 15% cross-linked carboxymethyl cellulose sodium in Example 4 is good, the accelerated stability for 6 months is qualified, and as the storage time increases, the release effect is still very good, the expansion rate remains unchanged, and the aging of the sustained-release coating is offset.

Claims

1. A method for preparing a lacidipine solid dispersion, characterized in that: The preparation method comprises the following steps: respectively weighing the prescribed amount of lacidipine raw material medicine, polymer carrier material and plasticizer, grinding and mixing to prepare lacidipine solid dispersion.

2. The preparation method according to claim 1, characterized in that: The solid dispersion is prepared from the following components in weight percentage: 16-18% of lacidipine, 74-76% of a polymer carrier material, and 8-9% of a plasticizer.

3. The preparation method according to claim 1 or 2, characterized in that: The plasticizer is Span 20, and the polymer carrier material is hydroxypropylmethylcellulose acetate succinate.

4. The preparation method according to claim 1, characterized in that: The preparation method is a hot melt extrusion method, and the specific steps are as follows: weigh the prescribed amount of lacidipine, carrier material and plasticizer respectively, add them into a twin-screw hot melt extruder after mixing, extrude at a temperature of 100C to 130C and a speed of 20rpm / min, and after the extrudate is cooled, crush it and pass it through an 80-mesh sieve to obtain the solid dispersion.

5. A lacidipine membrane-controlled sustained-release pellet capsule, characterized in that: The lacidipine film-controlled sustained-release micropellet capsule contains the lacidipine solid dispersion according to claim 1; wherein the sustained-release coating of the micropellet capsule comprises Eurdragit RL30D, a plasticizer triethyl citrate and an anti-adhesive talc, and the pellet core comprises cross-linked sodium carboxymethyl cellulose and an excipient.

6. The lacidipine membrane-controlled sustained-release pellet capsule according to claim 5, characterized in that: The excipients are fillers such as microcrystalline cellulose, lactose or solubilizers such as sodium lauryl sulfate.

7. The lacidipine membrane-controlled sustained-release pellet capsule according to claim 5, characterized in that: The percentage of cross-linked sodium carboxymethyl cellulose in the pellet core of the micro-pellet capsule is 5-15% by weight.

8. The lacidipine membrane-controlled sustained-release pellet capsule according to claim 5, characterized in that: The weight ratio of Eurdragit RL30D: triethyl citrate: talcum powder is 10:1:1-2, and the coating weight gain is 13%-30%.

9. A lacidipine membrane-controlled sustained-release pellet capsule, characterized in that: Based on 1000 capsules, the micro-pellet prescription is:

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