CN109260224B - Parricalcitol soft capsule and preparation method thereof - Google Patents
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Abstract
The invention relates to a paricalcitol soft capsule and a preparation method thereof, belonging to the field of pharmaceutical preparations. The invention provides a paricalcitol soft capsule, which comprises active ingredients, an antioxidant and a solvent, wherein the active ingredients comprise paricalcitol and disodium monofluorophosphate. The invention optimally screens the formula of the paricalcitol soft capsule, adopts propylene glycol and water as solvents, simultaneously adopts two antioxidants of an oil-soluble antioxidant and a water-soluble antioxidant to effectively improve the stability of the paricalcitol soft capsule, and combines the paricalcitol and the disodium monofluorophosphate to treat osteoporosis, thereby obtaining unexpected synergistic effect.
Description
Technical Field
The invention relates to the field of pharmaceutical preparations, and in particular relates to a paricalcitol soft capsule and a preparation method thereof.
Background
Paricalcitol (paricalcol), chemical name (1R, 3R) -5- [ (2E) -2- [ (1R, 3aS, 7aR) -1- [ (E, 2R, 5S) -6-Hydroxy-5, 6-dimethyl-3-en-2-y 1] -7a-methyl-2, 3, 3a, 5, 6, 7-hexahydro-1H-inden-4-ylidine ] ethylidene ] cyclohexane-1, 3-diol, structural formula aS follows:
paricalcitol is an active vitamin D analogue, is an artificially synthesized vitamin D analogue with biological activity, modifies a calcitriol side chain (D2) and an A ring (19-nor), and can effectively inhibit the level of parathyroid hormone (PTH). Although the structure of paricalcitol is similar to that of calcitriol, compared with calcitriol, the paricalcitol can inhibit parathyroid hormone more quickly and durably, has small influence on calcium, phosphorus and calcium-phosphorus deposition, so continuous hypercalcemia is less generated, the curative effect of the paricalcitol in reducing aortic calcification and improving bone is better than that of calcitriol, and the paricalcitol can reduce the fatality rate, the hospitalization frequency and the hospitalization time of a patient, so that the paricalcitol is an excellent medicament for treating osteoporosis.
Paricalcitol was first marketed in the united states as an injectable formulation (Zemplar) in 1998, and in 2005, the FDA approved paricalcitol for the prevention and treatment of Secondary Hyperparathyroidism (SHPT). Paricalcitol exerts its corresponding physiological effects like vitamin D by binding to the Vitamin D Receptor (VDR). With the discovery of VDR expression in different tissues and the disclosure of corresponding physiological effects, a great deal of research shows that the paricalcitol has certain curative effects on SHPT, and other diseases such as kidney diseases, cardiovascular diseases, immune inflammatory reactions, tumors and the like.
The paricalcitol is insoluble in water, soluble in an organic solvent, very unstable in chemical property and sensitive to pH and oxygen. Currently, only two types of soft capsules and injection are paricalcitol. Stable soft capsule and injection type are in great demand.
CN106474086A discloses a soft capsule pharmaceutical composition containing paricalcitol, the content is composed of paricalcitol, absolute ethyl alcohol, dibutyl hydroxy toluene and medium chain triglyceride, the rubber is composed of dry gelatin, glycerin, titanium dioxide and yellow ferric oxide, and the soft capsule is characterized in that the weight ratio of paricalcitol to absolute ethyl alcohol in the content is 1:600-800, the weight ratio of paricalcitol to dibutyl hydroxy toluene is 1: 8.5-15, the weight ratio of the paricalcitol to the medium chain triglyceride is in the range of 1: 71000-; the rubber comprises the following components in percentage by weight: glycerol: titanium dioxide: yellow iron oxide ═ 1: 0.3-0.8: 0.005-0.04: 0.001-0.008, preferably dry gelatin: glycerol: titanium dioxide: yellow iron oxide ═ 1: 0.45-0.55: 0.01-0.02: 0.0045-0.0055, most preferably dry gelatin: glycerol: titanium dioxide: yellow iron oxide ═ 1: 0.5: 0.015: 0.005; the gelatin is type A gelatin, and the water content of the gelatin capsule shell is 9-19%. The specific prescription can greatly shorten the disintegration time of the paricalcitol soft capsule.
CN104162168A discloses a stable paricalcitol pharmaceutical composition and a preparation method thereof, which is characterized in that the pharmaceutical composition contains 0.007-0.5% by weight of paricalcitol cyclodextrin inclusion compound, wherein the proportion of paricalcitol and cyclodextrin is 2: 1-200: 1 by weight, the instability of the pharmaceutical composition to oxygen and moisture is improved by prescription and process, the prepared tablet product has stable quality, higher dissolution rate, rapid dissolution in gastric juice and rapid effect.
CN107875134A discloses a liquid hard capsule of paricalcitol, which is mainly filled with a hard capsule shell. The paricalcitol pharmaceutical composition is mainly prepared from 0.25-4 parts by weight of paricalcitol, 720-1500 parts by weight of lower alcohol solvent, 50000-290000 parts by weight of oily matrix and 8-20 parts by weight of antioxidant. The process is simple, the operation conditions are easy to meet, the operation steps are closely connected, the process parameters are easy to control, no waste is generated, and the production process is green and environment-friendly. The capsule has good content uniformity, stable quality, long shelf life and high bioavailability.
The above prior arts do not solve the stability problem of the paricalcitol soft capsule well, and the research of using the combination of paricalcitol and disodium monofluorophosphate for treating osteoporosis is not available in the prior art.
Disclosure of Invention
The invention aims to provide a paricalcitol soft capsule with strong stability and excellent effect and a preparation method thereof.
In order to solve the technical problem, the technical scheme provided by the application is that the content of the paricalcitol soft capsule comprises an active ingredient, an antioxidant and a solvent, wherein the active ingredient comprises paricalcitol and disodium monofluorophosphate.
The weight part ratio of the paricalcitol to the disodium monofluorophosphate is 2-10:1-5, and preferably 2: 1.
The solvent consists of water and propylene glycol, wherein the water content is 10-20 wt%, the propylene glycol content is 80-90 wt%, preferably the water content is 15 wt%, and the propylene glycol content is 85 wt%.
The antioxidant includes a water-soluble antioxidant and an oil-soluble antioxidant.
The water-soluble antioxidant is selected from sodium metabisulfite, sodium bisulfite, sodium sulfite and sodium thiosulfate.
The oil-soluble antioxidant is selected from the group consisting of t-butyl p-hydroxyanisole (BHA), dibutyl cresol (BHT), vitamin E and lecithin.
Preferably, the antioxidant comprises sodium metabisulfite and dibutyl cresol.
The capsule shell of the paricalcitol soft capsule comprises a gelling agent, a plasticizer, a preservative, a coloring agent and water.
The gel comprises one or more of Arabic gum, xanthan gum, gellan gum, gelatin and carrageenan, the plasticizer comprises one or more of glycerol, sorbitol and stearic acid, the preservative comprises one or more of methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate and phenethyl alcohol, and the colorant comprises one or more of carmine, iron oxide red and lemon yellow.
The invention also provides a preparation method of the paricalcitol soft capsule, which comprises the following steps:
(1) weighing gel, plasticizer and water, heating in a gel melting cylinder, stirring, vacuum degassing, adding antiseptic and colorant, sampling, measuring water content and viscosity, cooling to 50-70 deg.C, and keeping the temperature;
(2) weighing paricalcitol and disodium monofluorophosphate, adding into solvent, heating in water bath at 60-80 deg.C, slowly stirring, adding antioxidant, and naturally cooling to room temperature;
(3) and (3) putting the capsule shell prepared in the step (1) and the content prepared in the step (2) into a soft capsule machine, pelleting, drying, inspecting and packaging to obtain the capsule.
The invention has the beneficial effects that:
the invention optimally screens the formula of the paricalcitol soft capsule, adopts propylene glycol and water as solvents, simultaneously adopts two antioxidants of an oil-soluble antioxidant and a water-soluble antioxidant to effectively improve the stability of the paricalcitol soft capsule, and simultaneously combines the paricalcitol and the disodium monofluorophosphate to treat osteoporosis, thereby obtaining unexpected synergistic effect.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers. All percentages, ratios, proportions, or parts are by weight unless otherwise specified.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.
Test example preparation of a Parricalcitol Soft Capsule
Palicalcitol soft capsules were prepared according to the formulation of table 1 (1000 capsules).
TABLE 1 Parricalcitol Soft Capsule formulation
Experimental example Effect of Diparacalcitol Soft capsules on ovariectomized osteoporosis rats
Grouping experiments: 120 female SD rats of 200-220g at 4 months of age were selected and randomly divided into 8 groups of 15 rats each, which are respectively:
(1) in the blank control group, distilled water is used for replacing the medicine in the experimental process;
(2) a negative control group, wherein distilled water is used for replacing the medicament in the experimental process;
(3) a positive control group, wherein nilestriol is given in the experimental process, and the dosage is 1 mg/kg;
(4) example 1 group, soft capsules of example 1 were given in the course of the experiment at a dose of 5. mu.g/kg of total of paricalcitol and disodium monofluorophosphate;
(5) example 2 group, the soft capsules of example 2 were administered during the experiment at a dose of 5 μ g/kg total of paricalcitol and disodium monofluorophosphate;
(6) example 3 group, the soft capsules of example 3 were given in the course of the experiment at a dose of 5. mu.g/kg in total of paricalcitol and disodium monofluorophosphate;
(7) comparative example 1 group, the soft capsules of comparative example 1 were given in the course of the experiment at a dose of 5 μ g/kg of paricalcitol;
(8) comparative example 2 group, the soft capsules of comparative example 2 were given a dose of 5 μ g/kg of paricalcitol during the experiment.
Ovaries were retained in the placebo group and ovaries were removed from each of the remaining groups.
The experimental method comprises the following steps: each group of animals was administered orally 1 time per day for 1 month, rats were anesthetized with 10% chloral hydrate, skin and muscle were incised at the abdomen, abdominal cavity was exposed, blood was taken from abdominal artery, serum was separated, uterus was rapidly peeled off, and the weight was weighed. The right tibia was removed, the attached muscle and other tissues were removed, and stored in 70% ethanol for determination of bone density.
The experimental results are as follows:
(1) bone Density and bone content determination
Bone density and bone content were determined. The measurement results are shown in tables 2 and 3.
TABLE 2 results of bone Density determination in ovariectomized osteoporosis rats
According to the results, the negative control group is not effectively treated due to the removal of ovaries, the indexes are reduced compared with the blank control group, the comparative examples 1-2 have certain effects of improving the total bone density, the trabecular bone density and the cortical bone density, and the effects of the examples 1-3 are obviously enhanced compared with the comparative examples 1-2.
TABLE 3 bone content determination results for ovariectomized osteoporosis rats
According to the results, the comparative examples 1-2 have certain effects of improving the total bone content, the trabecular bone content and the cortical bone content, while the effects of the examples 1-3 are obviously enhanced compared with the comparative examples 1-2, which shows that the combined use of the paricalcitol and the disodium monofluorophosphate generates a synergistic effect.
(2) Serum calcitonin and osteocalcin content determination
The fundus venous plexus blood sampling is carried out before and after 3 months of operation respectively, and the radioimmunoassay is adopted for determination. The measurement results are shown in tables 4 and 5.
TABLE 4 serum calcitonin assay results of ovariectomized osteoporosis rats
| Group of | Before operation (ng/L) | Three months after operation (ng/L) |
| Blank control group | 240.78±15.15 | 241.66±17.21 |
| Negative control group | 236.15±12.51 | 214.43±18.22 |
| Positive control group | 238.17±18.22 | 466.44±18.15 |
| EXAMPLE 1 group | 236.34±15.15 | 459.44±14.27 |
| EXAMPLE 2 group | 238.14±20.22 | 460.15±16.14 |
| EXAMPLE 3 group | 239.21±18.31 | 461.16±18.15 |
| Comparative example 1 group | 237.17±10.27 | 341.13±16.26 |
| Comparative example 2 group | 238.31±12.46 | 325.16±25.61 |
According to the results, the serum calcitonin contents of the groups before the operation are equivalent, the serum calcitonin content of the negative control group is reduced three months after the operation, the serum calcitonin content of the comparative examples 1-2 is increased, and the serum calcitonin content of the examples 1-3 is increased to the maximum extent.
TABLE 5 measurement results of osteocalcin content in ovariectomized osteoporosis rat
According to the results, the preoperative osteocalcin of each group is equivalent, the postoperative serum osteocalcin of the negative control group is reduced, the serum osteocalcin content of the comparative examples 1-2 is increased, and the serum osteocalcin content of the examples 1-3 is increased to the maximum extent.
(3) Determination of serum estradiol content
The fundus venous plexus blood sampling is carried out before and after 3 months of operation respectively, and the radioimmunoassay is adopted for determination. The results are shown in Table 6.
TABLE 6 serum estradiol content determination results for ovariectomized osteoporosis rats
| Group of | Before operation (pg/mL) | Three months after operation (pg/mL) |
| Blank control group | 14.21±2.11 | 14.15±3.16 |
| Negative control group | 13.98±1.38 | 8.21±3.14 |
| Positive control group | 14.28±2.46 | 21.42±2.16 |
| EXAMPLE 1 group | 14.16±3.01 | 21.38±1.87 |
| EXAMPLE 2 group | 13.89±3.14 | 22.01±1.78 |
| EXAMPLE 3 group | 14.29±3.22 | 21.78±2.16 |
| Comparative example 1 group | 13.99±2.14 | 16.18±2.15 |
| Comparative example 2 group | 14.21±3.15 | 16.29±1.88 |
According to the results, the preoperative serum estradiol content of each group is equivalent, the postoperative serum estradiol content of the negative control group is obviously reduced, the serum estradiol of the positive control group is increased, the serum estradiol of the comparative examples 1-2 is increased, the serum estradiol of the examples 1-3 is increased to the maximum extent, and the synergistic effect is generated when the serum estradiol content of each group is equivalent to that of the positive control group.
(4) Determination of serum calcium and phosphorus content
The fundus venous plexus blood sampling is carried out before and after 3 months of operation respectively, and the blood is measured by an enzyme labeling method. The results are shown in tables 7 and 8.
TABLE 7 measurement results of calcium content in ovariectomized osteoporosis rats
| Group of | Before operation (mmol/L) | Three months after operation (mmol/L) |
| Blank control group | 4.38±2.11 | 4.42±1.32 |
| Negative control group | 4.41±1.15 | 4.04±1.35 |
| Positive control group | 4.29±0.58 | 4.82±1.35 |
| EXAMPLE 1 group | 4.33±0.59 | 4.78±2.11 |
| EXAMPLE 2 group | 4.28±0.81 | 4.78±1.21 |
| EXAMPLE 3 group | 4.30±1.25 | 4.77±2.12 |
| Comparative example 1 group | 4.31±0.27 | 4.57±0.75 |
| Comparative example 2 group | 4.32±0.65 | 4.61±0.39 |
TABLE 8 phosphorus content determination results for ovariectomized osteoporosis rats
| Group of | Before operation (mmol/L) | Three months after operation (mmol/L) |
| Blank control group | 1.78±0.38 | 1.79±1.22 |
| Negative control group | 1.79±1.21 | 1.34±2.13 |
| Positive control group | 1.80±0.38 | 1.96±1.21 |
| EXAMPLE 1 group | 1.76±1.41 | 1.98±1.44 |
| EXAMPLE 2 group | 1.76±1.21 | 2.14±1.21 |
| EXAMPLE 3 group | 1.76±1.22 | 2.01±2.14 |
| Comparative example 1 group | 1.79±0.21 | 1.82±0.27 |
| Comparative example 2 group | 1.77±1.21 | 1.88±1.22 |
From the above results, it can be seen that, three months after the operation, the serum calcium and phosphorus contents of the negative control group are decreased compared with the blank control group, and the serum calcium and phosphorus contents of the positive control group, the comparative examples 1-2 and the examples 1-3 are increased compared with the negative control group, wherein the increase of the groups of examples 1-3 is the largest, which shows that the synergistic effect of promoting calcium and phosphorus absorption and further bone formation is achieved.
(5) Serum alkaline phosphatase assay
The fundus venous plexus blood sampling is carried out before and after 3 months of operation respectively, and the blood is measured by an enzyme labeling method. The results are shown in Table 9.
TABLE 9 determination of the alkaline phosphatase content in ovariectomized osteoporosis rats
| Group of | Before operation (U/L) | Three months after operation (U/L) |
| Blank control group | 276.38±7.17 | 271.21±12.34 |
| Negative control group | 278.12±6.56 | 318.23±14.32 |
| Positive control group | 277.15±6.43 | 207.14±15.12 |
| EXAMPLE 1 group | 279.12±5.54 | 201.12±11.47 |
| EXAMPLE 2 group | 275.98±1.32 | 199.43±12.76 |
| EXAMPLE 3 group | 279.21±2.43 | 200.13±18.88 |
| Comparative example 1 group | 281.22±7.43 | 251.15±15.65 |
| Comparative example 2 group | 280.32±6.37 | 256.31±32.13 |
According to the results, the serum alkaline phosphatase content of the positive control group is reduced compared with that of the negative control group after three months of operation, the serum alkaline phosphatase content of the comparative examples 1-2 and the examples 1-3 is also reduced compared with that of the negative control group, wherein the reduction range of the examples 1-3 is the largest and exceeds that of the positive control group.
(6) Uterine wet weight determination
After 3 months of operation, the cervical vertebra is quickly killed by dislocation, and then the uterus is weighed. The results are shown in Table 10.
TABLE 10 determination of uterine wet weight in ovariectomized osteoporosis rats
According to the results, the uterine wet weight of the positive control group, the comparative examples 1-2 and the examples 1-3 is obviously higher than that of the negative control group after three months of operation, which shows that the positive control group, the comparative examples 1-2 and the examples 1-3 all have the effect of increasing the blood estrogen level so as to promote the endometrial hyperplasia, wherein the effects of the examples 1-3 are optimal.
The foregoing is merely a preferred embodiment of the invention and is not intended to limit the scope of the invention, which is defined by the claims appended hereto, and any other technical entity or method that is encompassed by the claims as broadly defined herein, or equivalent variations thereof, is contemplated as being encompassed by the claims.
Claims (12)
1. The paricalcitol soft capsule is characterized in that the content comprises an active ingredient, an antioxidant and a solvent, wherein the active ingredient comprises paricalcitol and disodium monofluorophosphate, and the weight part ratio of the paricalcitol to the disodium monofluorophosphate is 2-10: 1-5.
2. The paricalcitol soft capsule according to claim 1, characterized in that the ratio by weight of paricalcitol and disodium monofluorophosphate is 2: 1.
3. The paricalcitol soft capsule according to claim 1 or 2, characterized in that the solvent consists of water and propylene glycol, the water content being 10-20 wt% and the propylene glycol content being 80-90 wt%.
4. The paricalcitol soft capsule according to claim 3, characterized in that the water content is 15 wt%.
5. The paricalcitol soft capsule according to claim 3, characterized in that the content of propylene glycol is 85 wt%.
6. The paricalcitol soft capsule according to any of claims 1-2, 4-5, characterized in that the antioxidant comprises a water soluble antioxidant and an oil soluble antioxidant.
7. The paricalcitol soft capsule according to any of claim 6, characterized in that the water soluble antioxidant is selected from sodium metabisulfite, sodium bisulfite, sodium sulfite and sodium thiosulfate.
8. The paricalcitol soft capsule according to claim 6, characterized in that the oil-soluble antioxidant is selected from the group consisting of tert-butyl p-hydroxyanisole (BHA), dibutyl cresol (BHT), vitamin E and lecithin.
9. The paricalcitol soft capsule according to claim 6, characterized in that the antioxidant comprises sodium metabisulfite and dibutyl cresol.
10. The paricalcitol soft capsule according to claim 1, characterized in that the capsule shell comprises gelling agents, plasticizers, preservatives, colorants and water.
11. The paricalcitol soft capsule according to claim 10, characterized in that the gelling agent comprises one or more of acacia, xanthan, gellan, gelatin and carrageenan, the plasticizer comprises one or more of glycerin, sorbitol and stearic acid, the preservative comprises one or more of methylparaben, ethylparaben and phenylethyl alcohol, and the colorant comprises one or more of carmine, red iron oxide and lemon yellow.
12. Process for the preparation of paricalcitol soft capsules according to any of claims 1 to 11, characterized in that it comprises the following steps:
(1) weighing gel, plasticizer and water, heating in a gel melting cylinder, stirring, vacuum degassing, adding antiseptic and colorant, sampling, measuring water content and viscosity, cooling to 50-70 deg.C, and keeping the temperature;
(2) weighing paricalcitol and disodium monofluorophosphate, adding into solvent, heating in water bath at 60-80 deg.C, slowly stirring, adding antioxidant, and naturally cooling to room temperature;
(3) and (3) putting the capsule shell prepared in the step (1) and the content prepared in the step (2) into a soft capsule machine, pelleting, drying, inspecting and packaging to obtain the capsule.
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| CN106474086A (en) * | 2015-09-01 | 2017-03-08 | 成都国弘医药有限公司 | A kind of pharmaceutical composition containing paricalcitol 19-Nor-1,25-dihydroxyvitamin D2 |
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|---|---|---|---|---|
| WO2006093545A1 (en) * | 2004-11-29 | 2006-09-08 | The Regents Of The University Of California | Activating extraction of demineralized bone matrix |
| CN101766709A (en) * | 2010-02-10 | 2010-07-07 | 涂雪莲 | Pharmaceutical composite for osteoporosis treatment and preparation method thereof |
| CN106474086A (en) * | 2015-09-01 | 2017-03-08 | 成都国弘医药有限公司 | A kind of pharmaceutical composition containing paricalcitol 19-Nor-1,25-dihydroxyvitamin D2 |
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