CN114939115A - Pharmaceutical composition and pellet and capsule prepared from same - Google Patents
Pharmaceutical composition and pellet and capsule prepared from same Download PDFInfo
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Abstract
The invention relates to the field of pharmaceutical preparations, and provides a pharmaceutical composition containing leflunomide or teriflunomide as an active ingredient and polyethylene glycol-32 stearate as a surfactant, and pellets and capsules prepared from the pharmaceutical composition, wherein the leflunomide or teriflunomide is preferably in a micronized form. The pharmaceutical composition and the pellet prepared from the pharmaceutical composition have high dissolution rate, can be used for oral administration and also can be administered through a nasogastric tube, and are particularly suitable for patients with mild to severe pneumonia caused by severe acute respiratory syndrome coronavirus (SARS-CoV, SARS-CoV-2), and more preferably patients with severe and severe pneumonia.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a pharmaceutical composition containing leflunomide or teriflunomide as an active ingredient, and pellets and capsules prepared from the pharmaceutical composition.
Background
Acute Respiratory infectious diseases caused by Severe Acute Respiratory Syndrome Coronavirus 2(Severe Acute Respiratory Syndrome Virus Coronavir 2, SARS-CoV-2, new Coronavirus for short) cause a novel Coronavirus pneumonia epidemic (new Coronavirus for short).
Dihydroorotate dehydrogenase (DHODH) inhibitors leflunomide (leflunomide) and teriflunomide (an active metabolite of leflunomide) have been widely used clinically for the treatment of various autoimmune diseases such as rheumatoid arthritis, lupus nephritis, multiple sclerosis, and the like. Experiments against novel coronaviruses described in the prior art show that leflunomide and teriflunomide can inhibit replication of the novel coronaviruses 2019-nCoV in vitro dose-dependently with EC50 of 41.49. mu. mol/L and 26.06. mu. mol/L respectively (Protein Cell 2020,11(10): 723-739). Leflunomide and teriflunomide have fewer side effects, can be taken for a long time, and can be developed into a proper preparation for treating the new coronary pneumonia.
However, leflunomide or teriflunomide, which is an active ingredient, is a poorly soluble drug, has extremely poor water solubility, and the dissolution rate thereof is difficult to increase by adopting a prescription and a preparation method of a common preparation, so that the bioavailability and the curative effect of the drug are influenced.
In addition, for clinically severe and critical patients with new coronary pneumonia, old people and children with dysphagia, the common oral preparation cannot meet the medication requirement, so that the anti-new coronary medicine which can be orally taken and also can be taken through a nasogastric tube is developed, can be suitable for treating the new coronary pneumonia in different degrees, improves the medication compliance of the patients, and has obvious clinical significance.
Disclosure of Invention
The inventor of the invention discovers that when the leflunomide or the teriflunomide is combined with the surfactant polyethylene glycol-32 stearate for use, the dissolution rate of the drug can be remarkably improved when the pharmaceutical preparation of the leflunomide and the teriflunomide is developed. Particularly, when leflunomide or teriflunomide is micronized, the particle size D90 is controlled to be below 10 mu m, and a surfactant polyethylene glycol-32 stearate is added, the improvement of the drug dissolution rate is particularly remarkable.
The invention provides a pharmaceutical composition, which comprises leflunomide or teriflunomide serving as an active ingredient and accounting for 5-50% of the total weight of the pharmaceutical composition, and further comprises a first surfactant, wherein the first surfactant is polyethylene glycol-32 stearate accounting for 5-50% of the total weight of the pharmaceutical composition. Wherein, leflunomide or teriflunomide is preferably 10 to 40 percent of the total weight of the pharmaceutical composition, and polyethylene glycol-32 stearate is preferably 20 to 50 percent of the total weight of the pharmaceutical composition.
The leflunomide or teriflunomide in the pharmaceutical compositions of the present invention is preferably micronized leflunomide or teriflunomide, which may be prepared by jet milling techniques, or micronized using other methods known in the art. The particle size D90 of the micronized leflunomide or the micronized teriflunomide is less than or equal to 10 mu m, preferably D90 is less than or equal to 8 mu m, more preferably D90 is less than or equal to 5 mu m, and most preferably D90 is less than or equal to 3 mu m.
In the pharmaceutical composition, the weight ratio of the micronized leflunomide or the micronized teriflunomide to the polyethylene glycol-32 stearate is 1: 1-1: 4, preferably 1: 1-1: 3.
The pharmaceutical composition of the invention further comprises a second surfactant, wherein the second surfactant is selected from tween, sodium dodecyl sulfate or a combination thereof.
In the pharmaceutical composition, the weight ratio of the first surfactant to the second surfactant is 25: 1-5: 1, preferably 20: 1-10: 1.
The pharmaceutical composition also comprises an adhesive which accounts for 1-5% of the total weight of the pharmaceutical composition, wherein the adhesive is selected from one or more of polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl starch, pregelatinized starch, polyethylene glycol and polyvinyl alcohol. Preferably one or more of polyvinylpyrrolidone, hydroxypropyl cellulose and hydroxypropyl methylcellulose.
The pharmaceutical composition also comprises a blank pill core accounting for 20-80% of the total weight of the pharmaceutical composition, wherein the blank pill core is selected from one or more of a sucrose pill core, a sucrose starch pill core, a silicon dioxide pill core or a microcrystalline cellulose pill core. The particle size of the blank pellet core is 0.18-0.3 mm.
The medicine composition can be prepared into oral preparations.
The invention also provides a pellet which is prepared from the medicinal composition, and the particle size of the prepared pellet is 0.2-0.6 mm, preferably 0.2-0.5 mm.
The pellet can be prepared by adopting a fluidized bed coating technology, for example, a first surfactant polyethylene glycol-32 stearate is slowly added into purified water at the temperature of 80-100 ℃, then a second surfactant is added, a homogenizer is adopted for emulsification and dispersion, after uniform dispersion, micronized leflunomide or teriflunomide and an adhesive are added, stirring is continued, a drug suspension is prepared, and the drug suspension is coated on a blank pellet core through a fluidized bed bottom spraying technology to prepare the drug-containing pellet.
The micro-pill can be further coated by a coating material to prepare a coated micro-pill, wherein the coating material is a gastric-soluble coating material, and the gastric-soluble coating material is selected from one or more of hydroxypropyl methylcellulose, polyvinyl alcohol, Ewing E100 or Ewing EPO. Further coating gastric-soluble coating material on the surface of the drug-containing pellet by a fluidized bed bottom spraying technology to prepare the coated pellet.
The pellet can be mixed with jam and beverage for swallowing, and can also be administrated by a nasal feeding tube. The pellet can be further encapsulated to prepare a capsule preparation. Namely, the invention further provides a capsule containing the pellet.
The pharmaceutical composition and the pellet prepared from the pharmaceutical composition are used for resisting RNA viruses, including but not limited to: coronaviruses such as Severe acute respiratory syndrome coronavirus (SARS-CoV), Merscov and 2019 New coronavirus (2019-nCoV), Ebola virus, bunyavirus, avian influenza H9N2, H1N1, H7N9, arenavirus, rabies virus, hepatitis C HCV, hepatitis B HBV, human immunodeficiency virus HIV-1, herpes simplex virus HSV-1, HSV-2 and the like. Preferably, the RNA virus is 2019 neocoronavirus (2019-nCoV), ebola virus, avian influenza H9N2, H1N1, or H7N 9. It is preferably used for treating severe acute respiratory syndrome coronavirus (SARS-CoV, SARS-CoV-2) from mild to severe pneumonia, more preferably severe or severe pneumonia.
The pharmaceutical composition and the pellet prepared from the pharmaceutical composition are clinically used for resisting novel coronavirus, wherein the dose of leflunomide is 2-300 mg/day, and the dose of teriflunomide is 1-200 mg/day; the dosage of leflunomide is preferably 10-100 mg/day, and the dosage of teriflunomide is preferably 7-70 mg/day.
The more preferable taking mode of the leflunomide pharmaceutical composition is 100 mg/day, and after the leflunomide pharmaceutical composition is continuously taken for three days, the dosage is adjusted to 10 mg or 20 mg/day, and the leflunomide pharmaceutical composition is continuously taken for 7-14 days.
The more preferable taking mode of the teriflunomide pharmaceutical composition is 70 mg/day, and after the teriflunomide pharmaceutical composition is continuously taken for three days, the dosage is adjusted to be 7 mg or 14 mg/day, and the teriflunomide pharmaceutical composition is continuously taken for 7-14 days.
The pharmaceutical compositions of the present invention may further be used in combination with other antiviral drugs including, but not limited to, one or more of lopinavir, oseltamivir (tamiflu), virperamivir, abidol and chloroquine (chloroquine phosphate), ribavirin (ribavirin), penciclovir (penciclovir), ridiflovir (remdesivir, GS-5734), favipiravir (favipiravir, T-705), nitazoxanide (nitazoxanide), nafamostat (nafamostat) and chloroquine (chloroquine), nimartrevir (nittrevir), ritonavir (ritonavir), Paxlovid, Molnupiravir, and the like; one or more of ribavirin (ribavirin), penciclovir (penciclovir), reiciclovir (remdesivir, GS-5734), favipiravir (favipiravir, T-705), nitazoxanide (nitazoxanide), nafamostat (nafamostat), nimatovir (nitratrelvir), ritonavir (ritonavir), Paxlovid, Molnupiravir are preferred.
The pharmaceutical composition has fast dissolution and high dissolution, and the accumulative dissolution of the drug is more than 90 percent within 60 minutes under the dissolution condition of basket method 100rpm by taking phosphate with pH6.8 as a dissolution medium. The pharmaceutical composition has good bioavailability and stability, and is easy for industrialization. The pharmaceutical composition and the pellets and the capsules prepared from the pharmaceutical composition can be orally taken, and have obvious clinical advantages for clinically patients with severe and critical coronary pneumonia, old people and children with dysphagia, and the preparation cannot meet the medication requirements, and can be taken through a nasogastric tube.
Examples
The present invention is further illustrated in detail below with reference to specific examples, which are provided for illustration only and do not limit the scope of the present invention in any way.
The test methods and apparatuses in the following examples are conventional methods and apparatuses unless otherwise specified, and the raw materials, reagent materials, and the like used in the following examples are commercially available products unless otherwise specified.
EXAMPLE 1 preparation and Properties of pharmaceutical compositions containing micronized leflunomide
1.1 preparation of micronized leflunomide
Micronizing the leflunomide raw material medicine by adopting a jet mill. Setting the milling Pressure (Mill Pressure) to be 0.2-0.4 MPa, and adjusting the milling Pressure to obtain different particle size distributions. The particle size distribution of the obtained micronized leflunomide was measured by laser diffraction and the results are shown in table 1.
TABLE 1 particle size distribution of micronized leflunomide batches
| Batch numbering | Active ingredient | D 90 (μm) |
| 1 | Micronized leflunomide | 87 |
| 2 | Micronized leflunomide | 35 |
| 3 | Micronized leflunomide | 8 |
| 4 | Micronized leflunomide | 3 |
1.2 preparation of micronized leflunomide pharmaceutical compositions
The micronized leflunomide of each batch is prepared into tiny pellets respectively and filled into capsules. The prescription is shown in Table 2.
TABLE 2 pharmaceutical composition Unit dose prescription (mg) containing micronized leflunomide
Preparation of pharmaceutical compositions of formula 1 to formula 4: weighing 20g of micronized leflunomide, 4g of polyvinylpyrrolidone (PVPK) 30 and 80g of purified water, sequentially adding the micronized leflunomide and the polyvinylpyrrolidone (PVPK) 30 into the purified water, and magnetically stirring to obtain a drug suspension for later use; weighing 60g of sucrose pellet cores (0.2-0.3 mm), placing the sucrose pellet cores in a fluidized bed for preheating, coating the medicine suspension on the surfaces of the sucrose pellet cores by a fluidized bed bottom spray coating technology, and drying the sucrose pellet cores by the fluidized bed to obtain medicine-containing pellets, wherein the diameter of the prepared medicine-containing pellets is 0.2-0.6 mm; the prepared drug-containing pellets are manually filled into capsules for standby.
1.3 dissolution determination of micronized leflunomide pharmaceutical compositions
The dissolution curve was measured by the first basket method of 0931, the four-part general rule of 2020 edition under the following conditions:
dissolution medium: phosphate buffer solution with pH6.8
Volume of medium: 900ml of
Temperature: 37 +/-0.5 DEG C
Rotating speed: 100rpm
The capsules of formula 1 to formula 4 were taken 6 capsules, respectively, and the dissolution curves were determined, the results are shown in table 3 below:
TABLE 3 in vitro dissolution assay for micronized leflunomide pharmaceutical compositions
The results in Table 3 show that when micronized leflurineDecimeter particle diameter D 90 When the particle size is controlled to be below 10 mu m, the in-vitro dissolution of leflunomide is obviously improved, but the dissolution of the drug is still incomplete within 60min, and further improvement on the prescription is needed.
Example 2 further preparation and Properties of pharmaceutical compositions containing micronized leflunomide
2.1 preparation of micronized leflunomide pharmaceutical compositions
Containing micronized leflunomide (D) 90 < 10 μm), as specified in the following table:
TABLE 4 pharmaceutical composition Unit dose prescription (mg) containing micronized leflunomide
Preparation of recipe 5 and recipe 6: weighing 20g of leflunomide, 4g of polyvinylpyrrolidone (PVPK) 30, 0.4g of tween 80 and 80g of purified water, sequentially adding the leflunomide, the polyvinylpyrrolidone and the tween 80 into the purified water, and magnetically stirring to obtain a drug suspension for later use; weighing 60g of sucrose pellet cores (0.2-0.3 mm), placing the sucrose pellet cores in a fluidized bed for preheating, coating the medicine suspension on the surfaces of the sucrose pellet cores by a fluidized bed bottom spray coating technology, and drying the medicine suspension by the fluidized bed to obtain medicine-containing pellets with the diameter of 0.2-0.6 mm; the prepared drug-containing pellets are manually filled into capsules for standby.
Preparation of recipe 7 and recipe 8: 40g of polyethylene glycol-32 stearate are weighed out and slowly added to 80g of 80 DEG C
Purified water at the temperature of 100 ℃ below zero is added with 0.4g of Tween 80, emulsified and dispersed by a homogenizer, after uniform dispersion, 20g of micronized leflunomide and 4g of polyvinylpyrrolidone PVPK30 are added, and the mixture is stirred uniformly to obtain a drug suspension for later use; weighing 60g of sucrose pellet cores (0.2-0.3 mm), placing the sucrose pellet cores in a fluidized bed for preheating, coating the medicine suspension on the surfaces of the sucrose pellet cores by a fluidized bed bottom spray coating technology, and drying the sucrose pellet cores by the fluidized bed to obtain medicine-containing pellets, wherein the diameter of the prepared medicine-containing pellets is 0.2-0.6 mm; the prepared drug-containing pellets are manually filled into capsules for standby.
2.2 dissolution determination of micronized leflunomide pharmaceutical compositions
The same as the dissolution rate measuring method of 1.3, 6 capsules of prescription 5 to prescription 8 are respectively taken, and the dissolution curve is measured, and the results are shown in the following table 5:
TABLE 5 in vitro dissolution assay for micronized leflunomide pharmaceutical compositions
| Time point (min) | Prescription 5 | Prescription 6 | Prescription 7 | Prescription 8 |
| 5 | 22.5 | 25.4 | 22.3 | 35.2 |
| 15 | 35.4 | 45.2 | 42.1 | 68.3 |
| 30 | 46.5 | 66.1 | 72.2 | 91.4 |
| 45 | 68.2 | 75.4 | 85.8 | 96.3 |
| 60 | 78.1 | 87.2 | 95.4 | 100.2 |
The results in Table 5 show that the addition of PEG-32 stearate allows for rapid dissolution of the drug in the dissolution medium when micronized leflunomide has a particle size D 90 When the particle size is controlled below 10 mu m, the cumulative dissolution of the drug is more than 95 percent within 60min, and when the particle size D of the micronized leflunomide is 90 Even when the particle size is 5 μm or less, the excellent effect of dissolving 100% is obtained.
Example 3 Effect of different ratios of micronized leflunomide/PEG-32 stearate on drug dissolution
3.1 preparation of micronized leflunomide pharmaceutical compositions
Containing micronized leflunomide (D) 90 3 μm), as specified in the following table:
TABLE 6 pharmaceutical composition Unit dose prescription (mg) containing micronized leflunomide
Preparation of formulation 9: weighing 20g of polyethylene glycol-32 stearate, slowly adding the 20g of polyethylene glycol-32 stearate into 80g of purified water at the temperature of 80-100 ℃, then adding 0.2g of tween 80, emulsifying and dispersing the mixture by a homogenizer, adding 20g of micronized leflunomide and 4g of polyvinylpyrrolidone (PVPK) 30 after uniform dispersion, and uniformly stirring the mixture for later use; weighing 60g of sucrose pellet cores (0.2-0.3 mm), placing the sucrose pellet cores in a fluidized bed for preheating, coating the medicine suspension on the surfaces of the sucrose pellet cores by a fluidized bed bottom spray coating technology, and drying the sucrose pellet cores by the fluidized bed to obtain medicine-containing pellets, wherein the diameter of the prepared medicine-containing pellets is 0.2-0.6 mm; the prepared drug-containing pellets are manually filled into capsules for standby.
Preparation of formulation 10: weighing 60g of polyethylene glycol-32 stearate, slowly adding the polyethylene glycol-32 stearate into 80g of purified water at the temperature of 80-100 ℃, then adding 0.6g of Tween 80, emulsifying and dispersing the mixture by a homogenizer, adding 20g of micronized leflunomide and 4g of polyvinylpyrrolidone (PVPK) 30 after uniform dispersion, and uniformly stirring the mixture for later use; weighing 60g of sucrose pellet cores (0.2-0.3 mm), placing the sucrose pellet cores in a fluidized bed for preheating, coating the medicine suspension on the surfaces of the sucrose pellet cores by a fluidized bed bottom spray coating technology, and drying the sucrose pellet cores by the fluidized bed to obtain medicine-containing pellets, wherein the diameter of the prepared medicine-containing pellets is 0.2-0.6 mm; the prepared drug-containing pellets are manually filled into capsules for standby.
Preparation of formulation 11: weighing 80g of polyethylene glycol-32 stearate, slowly adding the polyethylene glycol-32 stearate into 80g of purified water at the temperature of 80-100 ℃, then adding 0.8g of Tween 80, emulsifying and dispersing the mixture by a homogenizer, adding 20g of micronized leflunomide and 4g of polyvinylpyrrolidone (PVPK) 30 after uniform dispersion, and uniformly stirring the mixture for later use; weighing 60g of sucrose pellet cores (0.2-0.3 mm), placing the sucrose pellet cores in a fluidized bed for preheating, coating the drug suspension on the surfaces of the sucrose pellet cores through a fluidized bed bottom spray coating technology, and drying the drug suspension through the fluidized bed to obtain drug-containing pellets, wherein the diameter of the prepared drug-containing pellets is 0.2-0.6 mm; the prepared drug-containing pellets are manually filled into capsules for later use.
3.2 dissolution determination of micronized leflunomide pharmaceutical compositions
As with the dissolution rate measuring method of 2.3, 6 capsules of prescription 9 to prescription 11 were taken respectively, and the dissolution profile was measured, and the results are shown in Table 7.
TABLE 7 in vitro dissolution assay for micronized leflunomide pharmaceutical compositions
When the ratio of the leflunomide to the polyethylene glycol-32 stearate is 1: 1-1: 4, the medicine can be quickly dissolved and completely dissolved, but when the dosage of the polyethylene glycol-32 stearate is too high, the preparation dispersion time is too long, so that the ratio of the leflunomide to the polyethylene glycol-32 stearate is preferably 1: 1-1: 3.
3.3 nasal feeding tube administration application of pharmaceutical composition containing micronized leflunomide
Before use, the micronized leflunomide-containing capsules prepared according to formulas 8 to 11 are opened, and the very small pellets are dispersed in purified water and delivered to a patient through a nasal feeding tube.
Example 4 other composition examples containing micronized leflunomide
The formulation containing different unit doses of micronized leflunomide is shown in table 8 below.
TABLE 8 micronized leflunomide pharmaceutical composition Unit dose prescription (mg/granule)
The formulation compositions of the pellets using different types of binders, surfactants and cores are shown in Table 9 below.
TABLE 9 micronized leflunomide pharmaceutical composition Unit dose prescription (mg)
After the pellets are prepared, Eiteqi E100, Eiteqi EPO or hydroxypropyl methylcellulose can be further adopted for coating, and the composition is shown in Table 10.
TABLE 10 micronized leflunomide pharmaceutical composition coating formulations (mg)
Example 5 preparation and Properties of pharmaceutical composition containing micronized Terifluoride
5.1 preparation of micronized Terifluoride
Micronizing the teriflunomide raw material by using a jet mill. Setting the milling Pressure (Mill Pressure) to be 0.5-0.3 MPa, and adjusting the milling Pressure to obtain different particle size distributions. The particle size distribution of the obtained micronized teriflunomide was measured by laser diffraction method, and the results are shown in table 11.
Table 11 particle size distribution of each batch of micronized teriflunomide
| Batch numbering | Active ingredient | D 90 (μm) |
| 1 | Micronized teriflunomide | 65 |
| 2 | Micronized teriflunomide | 19 |
| 3 | Micronized teriflunomide | 7 |
| 4 | Micronized teriflunomide | 3 |
5.2 preparation of micronized Terifluoride pharmaceutical compositions
The micronized leflunomide of each batch is prepared into tiny pellets respectively and filled into capsules. See table 12 for prescription.
TABLE 12 pharmaceutical composition unit dose prescription (mg) containing micronized teriflunomide
| Prescription 12 | Prescription 13 | Prescription 14 | Prescription 15 | |
| Micronized teriflunomide | 14 | 14 | 14 | 14 |
| Hydroxypropyl cellulose | 3 | 3 | 3 | 3 |
| Microcrystalline cellulose pellet core | 80 | 80 | 80 | 80 |
| Purified water | 100 | 100 | 100 | 100 |
| Particle size of teriflunomide | D 90 ＝65μm | D 90 ＝19μm | D 90 ＝7μm | D 90 ＝3μm |
Preparation of pharmaceutical compositions of prescription 12-prescription 15: weighing 14g of micronized teriflunomide, 3g of hydroxypropyl cellulose and 100g of purified water, sequentially adding the micronized teriflunomide and the hydroxypropyl cellulose into the purified water, magnetically stirring, and uniformly dispersing to obtain a drug suspension for later use; weighing 80g of microcrystalline cellulose pellet cores (0.18-0.25 mm), placing the microcrystalline cellulose pellet cores in a fluidized bed for preheating, coating the medicine suspension on the surfaces of the microcrystalline cellulose pellet cores through a fluidized bed bottom spray coating technology, and drying the microcrystalline cellulose pellet cores through the fluidized bed to obtain medicine-containing pellets, wherein the particle size of the prepared medicine-containing pellets is 0.2-0.5 mm; the prepared drug-containing pellets are manually filled into capsules for standby.
5.3 dissolution determination of micronized Terifluoride pharmaceutical composition
The dissolution curve was measured by the first basket method 0931, a four-part general rule in 2020 edition, using the following conditions:
dissolution medium: pH6.8 phosphate buffer
Volume of medium: 900ml
Temperature: 37 +/-0.5 DEG C
Stirring speed: 100rpm
The dissolution curves of 6 capsules of prescription 12 to prescription 15 were measured, and the results are shown in Table 13 below:
TABLE 13 in vitro dissolution assay for micronized teriflunomide pharmaceutical compositions
| Time point (min) | Prescription 12 | Prescription 13 | Prescription 14 | Prescription 15 |
| 5 | 8.1 | 17.5 | 22.8 | 28.4 |
| 15 | 16.2 | 29.5 | 37.2 | 43.1 |
| 30 | 19.8 | 36.2 | 59.8 | 62.1 |
| 45 | 30.5 | 47.8 | 70.1 | 76.5 |
| 60 | 39.1 | 55.9 | 77.8 | 80.2 |
The results in Table 13 show that when micronized teriflunomide has a particle size D 90 When the particle size is controlled below 10 μm, the dissolution of the drug is obviously improved. However, the medicine still has incomplete dissolution within 60min, and further improvement on the prescription is needed.
Example 6 further preparation and Properties of pharmaceutical composition containing micronized teriflunomide
6.1 preparation of micronized Terifluoride pharmaceutical compositions
Containing micronized teriflunomide (D) 90 7 μm) (recipe 16 c to 7 μm) of a pharmaceutical compositionThe components contained in the formulation 20) and the contents of the components are shown in the following table 14.
TABLE 14 pharmaceutical composition Unit dose prescription (mg) containing micronized teriflunomide
Preparation of a formula 16-20: weighing raw and auxiliary materials according to the formula amount which is 1000 times larger, slowly adding polyethylene glycol-32 stearate and hydroxypropyl methylcellulose into purified water at the temperature of 80-100 ℃, then adding tween 80, emulsifying and dispersing through a homogenizer, adding micronized teriflunomide after uniform dispersion, and stirring uniformly to obtain a drug suspension for later use; placing a microcrystalline cellulose pellet core (0.18-0.25 mm) in a fluidized bed for preheating, coating the medicine suspension on the surface of the microcrystalline cellulose pellet core by a fluidized bed bottom spray coating technology, and drying by the fluidized bed to obtain a medicine-containing pellet with the diameter of 0.2-0.5 mm; the prepared drug-containing pellets are manually filled into capsules for standby.
6.2 dissolution test of pharmaceutical composition containing micronized teriflunomide
The dissolution curve was measured by the first basket method 0931, a four-part general rule in 2020 edition, using the following conditions:
dissolution medium: phosphate buffer solution with pH6.8
Volume of medium: 900ml
Temperature: 37 +/-0.5 DEG C
Stirring speed: 100rpm
Respectively taking 6 capsules of sample 1 with the prescription of 16-20, and determining a dissolution curve, wherein the results are shown in the following table 15:
TABLE 15 in vitro dissolution assay for micronized teriflunomide pharmaceutical compositions
| Time point (min) | Prescription 16 | Prescription 17 | Prescription 18 | Prescription 19 | Prescription 20 |
| 5 | 33.5 | 37.2 | 30.2 | 38.9 | 35.4 |
| 15 | 67.2 | 70.2 | 69.3 | 73.0 | 76.9 |
| 30 | 85.2 | 88.0 | 90.1 | 93.1 | 93.1 |
| 45 | 99.1 | 96.2 | 99.3 | 99.9 | 100.2 |
| 60 | 100.0 | 99.8 | 100.2 | 100.6 | 100.3 |
As can be seen from table 15, the capsules prepared using the micronized teriflunomide pharmaceutical composition of the present invention exhibited very rapid drug dissolution, which was complete within 45 minutes.
Claims (12)
1. A pharmaceutical composition comprises leflunomide or teriflunomide serving as an active ingredient and accounting for 5-50% of the total weight of the pharmaceutical composition, and further comprises a first surfactant, wherein the first surfactant is polyethylene glycol-32 stearate accounting for 5-50% of the total weight of the pharmaceutical composition.
2. The pharmaceutical composition according to claim 1, wherein the leflunomide or teriflunomide is micronized leflunomide or micronized teriflunomide.
3. The pharmaceutical composition according to claim 2, wherein the micronized leflunomide or micronized teriflunomide has a particle size D 90 Less than or equal to 10 μm, preferably D 90 Less than or equal to 8 μm, more preferably D 90 Less than or equal to 5 mu m, most preferably D 90 ≤3μm。
4. The pharmaceutical composition according to claim 3, wherein the weight ratio of the micronized leflunomide or micronized teriflunomide to the polyethylene glycol-32 stearate is 1:1 to 1:4, preferably 1:1 to 1: 3.
5. The pharmaceutical composition of any one of claims 1 to 4, further comprising a secondary surfactant selected from Tween, sodium lauryl sulfate or a combination thereof.
6. The pharmaceutical composition according to claim 5, wherein the weight ratio of the first surfactant to the second surfactant is 25:1 to 5:1, preferably 20:1 to 10: 1.
7. The pharmaceutical composition according to claim 6, further comprising a binder in an amount of 1-5% by weight of the total pharmaceutical composition, wherein the binder is one or more selected from polyvinylpyrrolidone, hydroxypropylcellulose, hypromellose, sodium carboxymethyl starch, pregelatinized starch, polyethylene glycol, and polyvinyl alcohol.
8. The pharmaceutical composition according to claim 7, further comprising a blank pellet core which accounts for 20-80% of the total weight of the pharmaceutical composition, wherein the blank pellet core is one or more selected from sucrose pellet cores, sucrose starch pellet cores, silicon dioxide pellet cores or microcrystalline cellulose pellet cores, and the particle size of the blank pellet core is 0.18-0.3 mm.
9. A pellet prepared from the pharmaceutical composition of any one of claims 1 to 8, wherein the particle size of the pellet is 0.2 to 0.6mm, preferably 0.2 to 0.5 mm.
10. The pellet of claim 9, wherein the pellet is further coated with a coating material to form a coated pellet, wherein the coating material is a gastric-soluble coating material, and the gastric-soluble coating material is selected from one or more of hypromellose, polyvinyl alcohol, Eiteqi E100, and Eiteqi EPO.
11. The pellet of claim 9 or 10, wherein the pellet is for administration by nasogastric tube.
12. A capsule comprising the pellet of any one of claims 9 to 11.
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| US20030180352A1 (en) * | 1999-11-23 | 2003-09-25 | Patel Mahesh V. | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
| WO2008116135A2 (en) * | 2007-03-22 | 2008-09-25 | Cytotech Labs, Llc | Topical formulations having enhanced bioavailability |
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| US20030180352A1 (en) * | 1999-11-23 | 2003-09-25 | Patel Mahesh V. | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
| WO2008116135A2 (en) * | 2007-03-22 | 2008-09-25 | Cytotech Labs, Llc | Topical formulations having enhanced bioavailability |
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