Medicament for treating proventriculitis of poultry and preparation method thereof

Abstract

The invention relates to the technical field of poultry medicines, and particularly discloses a medicament for treating poultry proventriculitis and a preparation method thereof, the medicament comprises the following raw materials by weight: 8-20 parts of a compound antibiotic, 2-5 parts of a slow-release antibacterial drug, 60-70 parts of sodium chloride, 10-16 parts of magnesium sulfate and 5-10 parts of a modified corn starch premix. According to the medicament for treating the proventriculitis of the poultry, disclosed by the invention, the effective medicament can play a stable and efficient drug effect at the proventriculitis of the poultry, the formula is reasonable, and the treatment effect is exact.

Description

Technical Field

[0001] The invention relates to the technical field of drugs for poultry, and specifically discloses a medicament for treating poultry glandular gastritis and a preparation method thereof. Background Art

[0002] Gastroenteritis is a common disease in poultry, often occurring in broilers, followed by breeders, with an incidence rate of 7-28% and a mortality rate of 30-50%. The growth of affected chickens is stunted, the weight of the chickens varies, the feed intake is low, the chickens are emaciated, the chickens are poorly uniform, and the feces are passed through the feed. In severe cases, the chickens even die of exhaustion, causing great losses. The main cause is the decrease in the pH value of gastric juice, which leads to the proliferation of Helicobacter pylori. The strong acidity burns the glandular stomach and gizzard, which in turn causes inflammation, and in severe cases, leads to bleeding and ulcers. Secondly, there are viral factors such as avian infectious bronchitis virus and avian influenza virus. In addition, Candida albicans infection and some immunosuppressive diseases can also induce poultry glandular gastritis.

[0003] In the prior art, the incidence of glandular gastritis in chickens is often reduced by adding chemical additives, such as adding western medicine to control bacterial infection and inhibit gastric acid secretion. Invention patent CN113367247A discloses a method for preparing a feed additive for preventing broiler gizzard glandular gastritis, comprising: mixing chitosan and ascorbic acid aqueous solution uniformly, adding β-cyclodextrin under stirring, continuing stirring, feeding into a supercritical fluid expansion reactor, introducing carbon dioxide gas and spraying from a nozzle, adding complex vitamins, complex trace elements, astaxanthin, and probiotics and mixing uniformly, adjusting the water content, and obtaining a chitosan complex; peeling and crushing the root of Tripterygium wilfordii, adding water to soak, filtering to remove moisture, air-drying the surface, freezing treatment, slowly heating, standing, grinding, adding extracellular enzymes to ferment, filtering to obtain enzymatically hydrolyzed Tripterygium wilfordii; adding stearic acid, glyceride, and calcium chloride to an ethanol aqueous solution and stirring uniformly to obtain a coating solution; adding the enzymatically hydrolyzed Tripterygium wilfordii to the chitosan complex, stirring uniformly and then granulating, and then making pellets, and coating the pellets with the coating solution to obtain a feed additive for preventing broiler gizzard glandular gastritis. However, the chitosan complex has complex components and is prone to uneven distribution of drug components, resulting in unstable drug absorption.

[0004] In view of this, the present invention discloses a drug that can enable the efficacy drug to exert a stable and efficient efficacy in the glandular stomach of poultry and has a definite effect on treating poultry glandular gastritis, which is particularly important. Summary of the invention

[0005] In view of the defects of the prior art, the present invention discloses a medicament for treating poultry glandular gastritis and a preparation method thereof. The medicament disclosed in the present invention can enable the efficacy drug to exert a stable and efficient efficacy in the glandular stomach of poultry, has a reasonable formula, and has a definite therapeutic effect.

[0006] In order to achieve the above object, the technical solution adopted by the present invention is as follows:

[0007] On one hand, the present invention provides a medicament for treating poultry glandular gastritis, which comprises the following raw materials in parts by weight: 8 to 20 parts of compound antibiotics, 2 to 5 parts of sustained-release antibacterial drugs, 60 to 70 parts of sodium chloride, 10 to 16 parts of magnesium sulfate and 5 to 10 parts of modified corn starch premix.

[0008] In some embodiments of the present invention, the compound antibiotic is a combination of lincomycin hydrochloride and metronidazole.

[0009] Preferably, the mass ratio of lincomycin hydrochloride to metronidazole is 1:(0.8-1.2).

[0010] Further preferably, the mass ratio of lincomycin hydrochloride to metronidazole is 1:1.

[0011] In some embodiments of the present invention, the preparation steps of the sustained-release antibiotic are as follows:

[0012] (1) Mixing mesoporous silica nanoparticles and deionized water, heating to 25-30° C., adding dopamine hydrochloride under stirring, stirring for 10-15 min, adding Tris-HCl buffer with a pH of 8-9, stirring for 1-2 h, centrifuging, washing and drying to obtain modified mesoporous silica nanoparticles;

[0013] (2) Add acequinoxaline and an organic solvent into a reactor, stir, and then add the modified mesoporous silica nanoparticles of step (1), heat to 28-35° C. and stir for 10-30 min, then stir and mix at room temperature for 10-15 h, remove the organic solvent by rotary evaporation, and purify, wash and freeze-dry to obtain a sustained-release antibacterial drug.

[0014] In some embodiments of the present invention, in step (1), the mass ratio of the mesoporous silica nanoparticles to dopamine hydrochloride is 1:(0.6-1.2).

[0015] Preferably, in step (1), the mass ratio of the mesoporous silica nanoparticles to dopamine hydrochloride is 1:0.9.

[0016] Preferably, in step (1), the particle size of the modified mesoporous silica nanoparticles is 10 to 30 nm.

[0017] In some embodiments of the present invention, in step (2), the mass ratio of acequinoxaline to modified mesoporous silica nanoparticles is 1:(1-2).

[0018] Preferably, in step (2), the mass ratio of acequinoxaline to modified mesoporous silica nanoparticles is 1:1.5.

[0019] Mequindox, also known as chlorfenapyr, is a chemical synthetic veterinary drug that mainly inhibits harmful intestinal flora of livestock and poultry, improves protein utilization, and is beneficial to protein synthesis in livestock and poultry. However, due to its poor water solubility and rapid metabolic elimination, the efficacy of mequindox is limited and it is easy to cause adverse consequences such as excessive drug residues. The existing technology often prepares mequindox nano drugs such as mequindox nano emulsions for use in livestock and poultry. However, its drug loading is low and the effect of alleviating the rapid metabolic elimination of mequindox is still insufficient.

[0020] The present invention introduces dopamine hydrochloride to modify the surface of mesoporous silica nanoparticles, utilizes the abundant silicon-hydrogen bonds on the surface to perform pre-modification, and then mixes with mequindox to finally obtain a sustained-release antibiotic, which maintains high stability before reaching the glandular stomach of poultry, and significantly improves the efficacy utilization rate of mequindox. The possible reasons are that, on the one hand, the specific modified mesoporous silica nanoparticles further increase the drug loading when used as carriers, and their large specific surface area and pore structure promote the high dispersion and rapid dissolution of mequindox; on the other hand, thanks to the large number of hydrophilic groups brought in by dopamine hydrochloride, the biocompatibility of the sustained-release antibiotic is significantly improved, and the adhesion brought by dopamine hydrochloride cooperates to prolong the absorption time of the drug.

[0021] In some embodiments of the present invention, the preparation steps of the modified corn starch premix are as follows:

[0022] 1) corn starch, sodium hydroxide and stearic acid are mixed, ground and stirred for 1 to 3 minutes, anhydrous ethanol is added, stirred and mixed, heated to 100 to 120° C. and reacted for 1 to 3 hours, the pH is adjusted to neutral, washed, centrifuged and dried to obtain modified corn starch;

[0023] 2) The modified corn starch and polyethylene glycol in step 1) are stirred and mixed for 10 to 30 minutes to obtain a modified corn starch premix.

[0024] In some embodiments of the present invention, in step 2), the polyethylene glycol is a mixture of PEG400 and PEG4000.

[0025] Preferably, in step 2), the mass ratio of PEG400 to PEG4000 is 1:(0.5-1.5); more preferably 1:1.

[0026] Preferably, in step 1), the mass ratio of corn starch to stearic acid is 1:(0.1-0.2); more preferably 1:0.15.

[0027] In some embodiments of the present invention, in step 2), the mass ratio of the modified corn starch to polyethylene glycol is 1:(1.5-3).

[0028] Preferably, in step 2), the mass ratio of the modified corn starch to polyethylene glycol is 1:2.3.

[0029] As mentioned above, the sustained-release antibacterial drug prepared by modified mesoporous silica nanoparticles loaded with acequinol can effectively solve the problems of poor water solubility of acequinol, rapid metabolic elimination, and limited efficacy. However, mesoporous silica nanoparticles are prone to cause drastic fluctuations in the blood concentration of the loaded acequinol in the body, thereby affecting the stable efficacy of the drug. Although the active groups of dopamine hydrochloride modified in its structure can provide a certain compatibility and stabilization effect, its effect is very limited.

[0030] The present invention chemically modifies corn starch by introducing stearic acid, thereby further improving the stability of the modified corn starch and achieving a balance between dispersibility and viscosity. This may be because the hydrophilic hydroxyl groups on the corn starch molecular chain are replaced, and the introduction of a certain length of carbon chain reduces the sedimentation effect caused by its hygroscopic condensation. When it is used in combination with polyethylene glycol, while exerting the controlled release effect of polyethylene glycol as a hydrophilic gel material, the drug concentration fluctuation phenomenon easily caused by the modified mesoporous silica nanoparticles is jointly balanced, thereby achieving a longer drug residence time and a better drug efficacy utilization effect.

[0031] Another aspect of the present invention also provides a method for preparing a medicament for treating poultry glandular gastritis, comprising the following steps:

[0032] The sustained-release antibiotic and the modified corn starch premix are mixed, and then the compound antibiotic, sodium chloride and magnesium sulfate are added, and after mixing, tablets, microspheres or micropills are prepared.

[0033] Compared with the prior art, the present invention has the following beneficial effects:

[0034] (1) The medicament for treating poultry glandular gastritis disclosed in the present invention is added with a sustained-release antibiotic and a modified corn starch premix, so that the effective drug can exert a stable and efficient efficacy in the glandular stomach of poultry, has a reasonable formula, and has a definite therapeutic effect.

[0035] (2) The present invention introduces dopamine hydrochloride to modify the surface of mesoporous silica nanoparticles, utilizes the abundant silicon-hydrogen bonds on the surface for pre-modification, and then mixes with mequindox to finally obtain a sustained-release antibacterial drug that maintains a high stability before reaching the glandular stomach of poultry, thereby significantly improving the efficacy utilization rate of mequindox.

[0036] (3) The present invention chemically modifies corn starch by introducing stearic acid, thereby further improving the stability of the modified corn starch, achieving a balance between dispersibility and viscosity, and reducing the sedimentation of corn starch due to moisture absorption and coagulation. When it is used in combination with polyethylene glycol, it can balance the drug concentration fluctuation phenomenon easily caused by the modified mesoporous silica nanoparticles, thereby achieving a longer drug residence time and a better drug efficacy utilization effect. DETAILED DESCRIPTION

[0037] The present invention will be described below in conjunction with specific embodiments. It should be noted that the following embodiments are examples of the present invention and are only used to illustrate the present invention, but not to limit the present invention. Other combinations and various modifications within the concept of the present invention may be performed without departing from the spirit or scope of the present invention.

[0038] Unless otherwise specified, the reagents used below can be easily obtained from commercial companies. Among them, polyethylene glycol (PEG400, PEG4000) were purchased from Shandong Ruisheng Pharmaceutical Excipients Co., Ltd.; straight-chain corn starch was purchased from Henan Xinfuwang New Material Technology Co., Ltd.; and mesoporous silica nanoparticles were purchased from Bohuasi Nanotechnology Ningbo Co., Ltd.

[0039] Unless otherwise specified, the polyethylene glycol used below is a mixture of PEG400 and PEG4000 in a mass ratio of 1:1, and the average particle size of the modified mesoporous silica nanoparticles used is 20 nm.

[0040] If there is no special explanation, the post-processing steps such as "centrifugation", "washing", "drying", "purification" and "freeze drying" used below are routine operations of those skilled in the art and can be selected according to actual operations; Tris-HCl buffer with a pH of 8.5 can be prepared according to the routine operations of those skilled in the art.

[0041] Preparation Example 1

[0042] The preparation steps of sustained-release antibiotics are as follows:

[0043] (1) 10 g of mesoporous silica nanoparticles and 100 mL of deionized water were mixed, the temperature was raised to 27° C., 9 g of dopamine hydrochloride was added under stirring, the mixture was stirred for 12 min, 10 mL of Tris-HCl buffer with a pH of 8.5 was added, the mixture was stirred for 1.5 h, and the mixture was centrifuged, washed, and dried to obtain modified mesoporous silica nanoparticles;

[0044] (2) Add 1 g of acequinoxaline and 10 mL of acetone to the reactor, stir, then add 1.5 g of the modified mesoporous silica nanoparticles of step (1), stir for 20 min, and then stir and mix at room temperature for 13 h. Remove the acetone by rotary evaporation, and then purify, wash and freeze-dry to obtain a sustained-release antibacterial drug.

[0045] Preparation Example 2

[0046] The preparation steps of the sustained-release antibiotic are the same as those of Preparation Example 1, except that the amount of dopamine hydrochloride added in step (1) is 13 g.

[0047] Preparation Example 3

[0048] The preparation steps of the sustained-release antibacterial drug are the same as those of Preparation Example 1, except that the amount of modified mesoporous silica nanoparticles added in step (2) is 2.2 g.

[0049] Preparation Example 4

[0050] The preparation steps of modified corn starch premix are as follows:

[0051] 1) 10 g corn starch, 0.5 g sodium hydroxide and 1.5 g stearic acid were mixed, ground and stirred for 2 min, 20 mL anhydrous ethanol was added, stirred and mixed, the temperature was raised to 110 ° C. and reacted for 2 h, the pH was adjusted to neutral, washed, centrifuged and dried to obtain modified corn starch;

[0052] 2) 1 g of the modified corn starch prepared in step 1) and 2.3 g of polyethylene glycol were stirred and mixed for 20 min to obtain a modified corn starch premix.

[0053] Preparation Example 5

[0054] The preparation steps of the modified corn starch premix are the same as those of Preparation Example 4, except that the amount of stearic acid added in step 1) is 2.2 g.

[0055] Preparation Example 6

[0056] The preparation steps of the modified corn starch premix are the same as those of Preparation Example 4, except that the amount of polyethylene glycol added in step 2) is 3.3 g.

[0057] Preparation Example 7

[0058] The preparation steps of corn starch premix are as follows:

[0059] 1 g of corn starch and 2.3 g of polyethylene glycol were stirred and mixed for 20 minutes to obtain a corn starch premix.

[0060] Example 1

[0061] A medicament for treating poultry glandular gastritis comprises the following raw materials in parts by weight: 14 parts of compound antibiotics, 3.5 parts of sustained-release antibacterial drugs, 65 parts of sodium chloride, 14 parts of magnesium sulfate and 7.5 parts of modified corn starch premix.

[0062] The composite antibiotic used is obtained by mixing lincomycin hydrochloride and metronidazole in a mass ratio of 1:1, the sustained-release antibacterial drug used is obtained from Preparation Example 1, and the modified corn starch premix used is obtained from Preparation Example 4.

[0063] The preparation method of the medicament for treating poultry glandular gastritis in this embodiment comprises the following steps:

[0064] The sustained-release antibiotic and the modified corn starch premix are mixed, and then the compound antibiotic, sodium chloride and magnesium sulfate are added, mixed evenly, and then micro-pellets are prepared according to conventional techniques in the art.

[0065] Example 2

[0066] A medicament for treating poultry glandular gastritis comprises the following raw materials in parts by weight: 8 parts of compound antibiotics, 2 parts of sustained-release antibacterial drugs, 60 parts of sodium chloride, 10 parts of magnesium sulfate and 5 parts of modified corn starch premix.

[0067] The composite antibiotic used is obtained by mixing lincomycin hydrochloride and metronidazole in a mass ratio of 1:0.8, the sustained-release antibacterial drug used is obtained from Preparation Example 1, and the modified corn starch premix used is obtained from Preparation Example 4.

[0068] The preparation method of the medicament for treating poultry glandular gastritis in this example is the same as that in Example 1.

[0069] Example 3

[0070] A medicament for treating glandular gastritis in poultry comprises the following raw materials in parts by weight: 20 parts of compound antibiotics, 5 parts of sustained-release antibacterial drugs, 70 parts of sodium chloride, 16 parts of magnesium sulfate and 10 parts of modified corn starch premix.

[0071] The composite antibiotic used is obtained by mixing lincomycin hydrochloride and metronidazole in a mass ratio of 1:1.2, the sustained-release antibacterial drug used is obtained from Preparation Example 1, and the modified corn starch premix used is obtained from Preparation Example 4.

[0072] The preparation method of the medicament for treating poultry glandular gastritis in this example is the same as that in Example 1.

[0073] Example 4

[0074] A medicament for treating poultry glandular gastritis and a preparation method thereof. The specific implementation manner is the same as that of Example 1, except that the sustained-release antibiotic used is obtained from Preparation Example 2.

[0075] Example 5

[0076] A medicament for treating poultry glandular gastritis and a preparation method thereof. The specific implementation manner is the same as that of Example 1, except that the sustained-release antibiotic used is obtained from Preparation Example 3.

[0077] Example 6

[0078] A medicament for treating poultry glandular gastritis and a preparation method thereof. The specific implementation manner is the same as that of Example 1, except that the modified corn starch premix used is obtained from Preparation Example 5.

[0079] Example 7

[0080] A medicament for treating poultry glandular gastritis and a preparation method thereof. The specific implementation manner is the same as that of Example 1, except that the modified corn starch premix used is obtained from Preparation Example 6.

[0081] Comparative Example 1

[0082] A medicament for treating poultry glandular gastritis and a preparation method thereof. The specific implementation manner is the same as that of Example 1, except that an equal amount of acequinoxaline is used to replace the sustained-release antibiotic used.

[0083] Comparative Example 2

[0084] A medicament for treating poultry glandular gastritis and a preparation method thereof. The specific implementation manner is the same as that of Example 1, except that the modified corn starch premix used is replaced by an equal amount of the corn starch premix obtained in Preparation Example 7.

[0085] Performance Test:

[0086] The experiment selected 150 laying hens (white broilers) with glandular gastritis (average age of 30, average weight of 1.61 ± 0.3 kg, clinical manifestations: decreased feed intake, lack of energy, pale visible mucosa, propeller-shaped feathers, emaciation, weakness) and randomly divided them into 10 groups, each with 15, and 9 groups corresponding to the commercial feed mixed with 5wt% of the medicament prepared in the above-mentioned Examples 1-7 and Comparative Examples 1-2 were used as the test group, and free feeding was adopted. The control group was fed with water containing 5wt% amoxicillin soluble powder in a mixed drinking manner, and free drinking water was adopted. The other feeding conditions remained the same, and the medication was used for 5 consecutive days. The recovery of the laying hens was observed and recorded every day, and the average market weight for 42 days was recorded. The judgment criteria disclosed in CN104208089B were used to evaluate the medication effect. The specific results are shown in Table 1, and the judgment criteria are as follows:

[0087] (1) Cured: The clinical symptoms of the sick chickens disappeared, and their spirit and appetite returned to normal; (2) Effective: Most of the clinical symptoms of the sick chickens were alleviated or disappeared, and their appetite was restored; (3) Ineffective: The clinical symptoms of the sick chickens did not alleviate or even worsened;

[0088] Effective rate = {(number of effective cases + number of cured cases) / (number of cured cases + number of effective cases + number of ineffective cases)}×100%.

[0089] Table 1

[0090] project Average slaughter weight at 42 days (kg) Effectiveness (%) Example 1 2.97 96 Example 2 2.88 93 Example 3 2.92 94 Example 4 2.78 91 Example 5 2.81 90 Example 6 2.72 88 Example 7 2.59 87 Comparative Example 1 2.37 82 Comparative Example 2 2.21 80

[0091] As shown in Table 1, the medicaments for treating poultry proventriculus disclosed in Examples 1-3 of the present invention have significant efficacy, high effective rate, good growth of chickens, and high average slaughter weight at 42 days.

[0092] By comparing Example 4 and Example 5 with Example 1, it can be seen that when the addition amount of dopamine hydrochloride and modified mesoporous silica nanoparticles in the preparation of sustained-release antibacterial drugs is changed, the therapeutic effect will be affected, the growth of chickens will be affected, and the weight of the chickens will decrease after 42 days of slaughter. This is caused by the stability of the drug.

[0093] By comparing Example 6 and Example 7 with Example 1, it can be seen that when the amount of corn starch added to prepare the modified corn starch premix is ​​changed, the efficacy of the drug will be deteriorated, and the body weight of the pigs slaughtered at 42 days will decrease significantly;

[0094] From the comparison between Comparative Example 1 and Example 1, it can be seen that when the sustained-release antibiotic is replaced by an equal amount of acequinoxaline, the chicken may refuse to eat or eat less, which affects the therapeutic effect;

[0095] From the comparison between Comparative Example 2 and Example 1, it can be seen that when only the blend of corn starch and polyethylene glycol is used, the drug cannot exert a stable and efficient efficacy in the glandular stomach of chickens, the therapeutic effect is reduced, and the growth of chickens is affected.

[0096] The above description is only a preferred embodiment of the present invention and does not limit the present invention in any form. Although the present invention has been disclosed as a preferred embodiment as above, it is not used to limit the present invention. Any technician familiar with this profession can make some changes or modifications to equivalent embodiments of equivalent changes using the technical contents disclosed above without departing from the scope of the technical solution of the present invention. However, any simple modification, equivalent change and modification made to the above embodiments based on the technical essence of the present invention without departing from the content of the technical solution of the present invention still fall within the scope of the technical solution of the present invention.

Claims

1. A medicament for treating glandular gastritis in poultry, characterized in that: The medicament comprises the following raw materials in parts by weight: 8-20 parts of compound antibiotics, 2-5 parts of sustained-release antibacterial drugs, 60-70 parts of sodium chloride, 10-16 parts of magnesium sulfate and 5-10 parts of modified corn starch premix.

2. The medicament for treating poultry glandular gastritis according to claim 1, characterized in that: The compound antibiotic is a combination of lincomycin hydrochloride and metronidazole.

3. The medicament for treating poultry glandular gastritis according to claim 1, characterized in that: The preparation steps of the sustained-release antibiotic are as follows: (1) Mixing mesoporous silica nanoparticles and deionized water, heating to 25-30° C., adding dopamine hydrochloride under stirring, stirring for 10-15 min, adding Tris-HCl buffer with a pH of 8-9, stirring for 1-2 h, centrifuging, washing and drying to obtain modified mesoporous silica nanoparticles; (2) Add acequinoxaline and an organic solvent into a reactor, stir, and then add the modified mesoporous silica nanoparticles of step (1), heat to 28-35° C. and stir for 10-30 min, then stir and mix at room temperature for 10-15 h, remove the organic solvent by rotary evaporation, and purify, wash and freeze-dry to obtain a sustained-release antibacterial drug.

4. The medicament for treating poultry glandular gastritis according to claim 3, characterized in that: In step (1), the mass ratio of the mesoporous silica nanoparticles to dopamine hydrochloride is 1:(0.6-1.2).

5. The medicament for treating poultry glandular gastritis according to claim 3, characterized in that: In step (2), the mass ratio of acetoquinol to modified mesoporous silica nanoparticles is 1:(1-2).

6. The medicament for treating poultry glandular gastritis according to claim 1, characterized in that: The preparation steps of the modified corn starch premix are as follows: 1) corn starch, sodium hydroxide and stearic acid are mixed, ground and stirred for 1 to 3 minutes, anhydrous ethanol is added, stirred and mixed, heated to 100 to 120° C. and reacted for 1 to 3 hours, the pH is adjusted to neutral, washed, centrifuged and dried to obtain modified corn starch; 2) The modified corn starch and polyethylene glycol in step 1) are stirred and mixed for 10 to 30 minutes to obtain a modified corn starch premix.

7. The medicament for treating poultry glandular gastritis according to claim 6, characterized in that: In step 1), the mass ratio of corn starch to stearic acid is 1:(0.1-0.2).

8. The medicament for treating poultry glandular gastritis according to claim 6, characterized in that: In step 2), the polyethylene glycol is a mixture of PEG400 and PEG4000.

9. The medicament for treating poultry glandular gastritis according to claim 6, characterized in that: In step 2), the mass ratio of the modified corn starch to the polyethylene glycol is 1:(1.5-3).

10. A method for preparing a medicament for treating poultry proventriculus according to any one of claims 1 to 9, characterized in that: The following steps are involved: The sustained-release antibiotic and the modified corn starch premix are mixed, and then the compound antibiotic, sodium chloride and magnesium sulfate are added, and after mixing, tablets, microspheres or micropills are prepared.