CN110731952A - calcitriol patch and its preparation method - Google Patents
calcitriol patch and its preparation method Download PDFInfo
- Publication number
- CN110731952A CN110731952A CN201810787794.9A CN201810787794A CN110731952A CN 110731952 A CN110731952 A CN 110731952A CN 201810787794 A CN201810787794 A CN 201810787794A CN 110731952 A CN110731952 A CN 110731952A
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- CN
- China
- Prior art keywords
- calcitriol
- sensitive adhesive
- layer
- pressure
- patch
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
- A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7084—Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
Abstract
The invention discloses calcitriol patches and a preparation process thereof, wherein the patches are composed of a back lining layer, a drug storage layer and an anti-sticking layer, the drug storage layer comprises calcitriol, pressure-sensitive adhesive and percutaneous absorption enhancer, and the patches have excellent performances in transdermal absorption rate, mechanical property, preparation process, patient compliance and the like, and are used for preventing and treating senile osteoporosis and rickets in children.
Description
Technical Field
The invention relates to the field of pharmacy, in particular to calcitriol patches, and specifically relates to calcitriol patches which are composed of a back lining layer, a drug storage layer and an anti-sticking layer, have excellent performances in transdermal absorption rate, mechanical properties, preparation process, patient compliance and the like, and are used for preventing and treating senile osteoporosis and rickets in children.
Background
Calcitriol, also known as 1, 25-dihydroxyvitamin D3. It is an active metabolic hormone product of vitamin D3 in the human body. The biosynthesis pathway is that 7-dehydrocholesterol generates vitamin D3 after being irradiated by ultraviolet rays in skin, vitamin D3 forms 25-hydroxycholecalciferol under the action of hydroxylase system in liver, then the 25-hydroxycholecalciferol is transported to kidney through blood, and hydroxylase in proximal tubular cells of the kidney is hydroxylated into calcitriol by the 25-hydroxycholecalciferol.
Active vitamin D promotes intestinal calcium absorption, improves blood calcium concentration, provides raw materials for calcium deposition in bones and bone mineralization, plays an indirect role in bone formation, can also directly act on osteoblasts, and calcitriol receptors are relatively concentrated in the osteoblasts.
Calcitriol is a white or off-white crystalline compound, naturally exists in human bodies, is hardly soluble in water, is easily soluble in organic solvents, is sensitive to air, light and heat, is easily oxidized and degraded in the production and storage processes to generate various degradation products, is difficult to prepare because of being hardly soluble in water, and therefore, the solubility of calcitriol is improved, and the quantity and the content of the degradation products are reduced as much as possible, which is difficulties in the production process of the existing calcitriol preparation.
Disclosure of Invention
The invention aims to provide calcitriol patches which are composed of a back lining layer, a drug storage layer and an anti-adhesion layer, have excellent performances in transdermal absorption rate, mechanical property, preparation process, patient compliance and the like, are used for preventing and treating senile osteoporosis and rickets in children, can avoid stimulation of oral administration to gastrointestinal tracts, can increase percutaneous permeation of drugs, and release the drugs stably, is convenient to administer for elderly and children patients with dysphagia, can be used immediately after being pasted, only needs to remove the patches when administration is interrupted, and has good adhesion, flexibility and no stimulation.
The calcitriol patch comprises a back lining layer, a drug storage layer and an anti-adhesion layer, wherein the drug storage layer comprises main drugs of calcitriol, a pressure-sensitive adhesive and a percutaneous absorption enhancer, the calcitriol accounts for 0.010-0.032% of the solid content of the pressure-sensitive adhesive, the percutaneous absorption enhancer accounts for 1.0-20.0% of the solid content of the pressure-sensitive adhesive, the matrix material selected by the pressure-sensitive adhesive is or more compounds of silicone polymers, isobutylene polymers, acrylate polymers or cellulose, and the percutaneous absorption enhancer is or more of sulfoxides, pyrrolidones, laurocapram, fatty acids and esters thereof, surfactants, alcohols, polyols, terpenes, amines, amides, cyclodextrins and phospholipids.
or more of inert filler, plasticizer, tackifier or antioxidant can be added into the calcitriol patch, and the dosage of the calcitriol patch is 0-10% of the solid content of the pressure sensitive adhesive respectively.
The back lining layer of the calcitriol patch is an aluminum-containing polyethylene composite film or elastic non-woven fabric; the anti-sticking layer is a polyester film or paper with the surface treated by silicon oil anti-sticking treatment or containing fluorine.
The preparation process of the calcitriol patch comprises the steps of fully mixing calcitriol, pressure-sensitive adhesive and percutaneous absorption enhancer, coating the mixture on an anti-sticking layer, drying the mixture at 40-80 ℃, then compounding the dried mixture by using an aluminum-containing polyethylene composite film or an elastic non-woven fabric backing layer, and cutting the compounded mixture into pieces with certain size and specification to obtain the calcitriol patch.
Detailed description of the preferred embodiment
The following examples are merely illustrative of the present invention in further detail and are not to be construed as limiting the invention in any way.
TABLE 1 examples 1-4 recipe design
Examples 1
Weighing 0.032g of calcitriol, dissolving in 2.0g of absolute ethyl alcohol, adding 100.0g of silicone pressure-sensitive adhesive after dissolving, mixing and stirring for 1h, defoaming by a vacuum pump to obtain a uniform colloid solution, coating the colloid solution on a coating machine, adjusting the coating thickness to be 0.1mm, coating the coating on an anti-sticking layer, drying at 50 ℃ for 1h, then compounding the coating with an aluminum-containing polyethylene composite film or an elastic non-woven fabric backing layer, and punching into with fixed size and specification to obtain the medicine permeability after 12h of administration by high performance liquid chromatography.
EXAMPLES example 2
Weighing 0.032g of calcitriol, 0.030g of butyl hydroxyanisole and 0.030g of dibutyl hydroxytoluene, dissolving the calcitriol, 0.0g of propylene glycol, adding 100.0g of silicone pressure-sensitive adhesive after dissolving, mixing and stirring for 1h, defoaming by a vacuum pump to obtain a uniform colloid solution, coating the colloid solution on a coating machine to adjust the coating thickness to be 0.1mm, coating the coating on an anti-sticking layer, drying for 1h at 50 ℃, then compounding the coating with an aluminum-containing polyethylene composite film or an elastic non-woven fabric backing layer, and punching the coating into with fixed size and specification to obtain the medicine permeability after 12h administration by high performance liquid chromatography.
EXAMPLE 3
Weighing 0.010g of calcitriol, dissolving in 5.0g of laurocapram, adding 100.0g of polyisobutylene pressure-sensitive adhesive after dissolving, mixing and stirring for 1h, defoaming by a vacuum pump to obtain a uniform colloid solution, coating on a coating machine, adjusting the coating thickness to be 0.1mm, coating on an anti-sticking layer, drying at 50 ℃ for 1h, then compounding by using an aluminum-containing polyethylene composite membrane or an elastic non-woven fabric backing layer, and punching into with fixed size and specification to obtain the medicine permeability after the medicine is administered for 12 h.
EXAMPLE 4
Weighing 0.010g of calcitriol, 0.010g of butyl hydroxy anisole and 0.010g of dibutyl hydroxy toluene, dissolving in 10.0g of medium chain triglyceride, adding 100.0g of acrylic resin pressure sensitive adhesive after dissolving, mixing, stirring for 1h, defoaming by a vacuum pump to obtain a uniform colloid solution, coating the colloid solution on a coating machine to adjust the coating thickness to be 0.1mm, coating the coating solution on an anti-sticking layer, drying for 1h at 50 ℃, then compounding by using an aluminum-containing polyethylene composite film or an elastic non-woven fabric backing layer, and punching into with a fixed size and specification to obtain the medicine permeability after 12h administration by high performance liquid chromatography.
In order to compare the drug permeability, adhesion and safety of examples 1 to 4, a transdermal absorption test, an initial adhesion and permanent adhesion test and a skin irritation test were performed, respectively.
Transdermal absorption test the present invention adopts Franz horizontal diffusion cell, nude mouse abdomen skin as barrier, and receiving medium of 0.5% Tween80 water solution, and high performance liquid chromatography to measure the medicine permeability after 12 hr administration, with the following chromatographic conditions.
The instrument comprises the following steps: daian U3000 high-performance liquid chromatograph equipped with ultraviolet detector
A chromatographic column: waters Symmetry C18 column, 4.6X 250mm, 5 μm
Mobile phase: a = acetonitrile-water (85-15); b = acetonitrile-water (55-45)
Detection wavelength: 265nm
Flow rate: 1.0ml/min
Sample introduction amount: 20 mu l
Column temperature: 35 deg.C
Operating time: 40min
Gradiometer:
results of transdermal tests of calcitriol patches prepared in examples 1-4 are shown in table 2. The results show that the calcitriol patch releases smoothly, and the patch with the transdermal penetration enhancer in the prescription releases calcitriol more. The antioxidant had no effect on the release of calcitriol.
Table 2 results of drug permeation of calcitriol patches prepared in examples 1-4 (n = 6)
| Parameter(s) | Examples 1 | EXAMPLES example 2 | EXAMPLE 3 | EXAMPLE 4 |
| Q12h (ng/cm2) | 18.60 ±3.71 | 22.78 ±5.29 | 39.15 ±3.56 | 29.15 ±3.56 |
| J (ng/cm2/h) | 1.39 ±0.45 | 1.53 ±0.61 | 3.25 ±0.32 | 2.25 ±0.32 |
| T lag(h) | 0 | 0.22±0.24 | 0.01±0.04 | 0.15±0.11 |
Initial adhesion and permanent adhesion tests refer to the methods of GB4852-84 and GB/T4851-1998, respectively, and the test results are shown in Table 3. The results show that the initial adhesion and the permanent adhesion of the examples 1-4 have no significant difference, and the patch prepared by the formula with the penetration enhancer is good in drug permeability.
TABLE 3 initial and sustained tack test results for calcitriol patches prepared in examples 1-4
| Parameter(s) | Examples 1 | EXAMPLES example 2 | EXAMPLE 3 | EXAMPLE 4 |
| Initial adhesionNote 1 | 19# ball | 18# ball | 19# ball | 19# ball |
| Permanent adhesionNote 2 | 208min | 196min | 187min | 190min |
Note 1: and (3) detecting initial adhesion: the method of GB4852-84 was used.
Note 2: and (3) permanent adhesion detection: method adopting GB/T4851-1998
Skin irritation test
The weight of the test animal guinea pig is 180 g-220 g, and the test animal guinea pig is male and female. In the 24 hours before the test, the guinea pigs were depilated on both sides of the dorsal spine with an area of 2cm 2cm on each side. Selecting guinea pigs without skin damage as intact skin group test animals 24h after depilation; the skin of the dehaired guinea pig was scratched with sandpaper to bleed and used as a test animal in the damaged skin group.
The test of the administration method is divided into a complete skin group and a damaged skin group, 10 of each group adopts self left and right control, namely, the left hairless area is pasted with calcitriol patch, the right area is smeared with normal saline, after the tested drug is administered for 24h, the residual tested drug is clear by distilled water, the skin condition of the administration part of the hairless area is observed and recorded for 1h, 24h, 48h and 72h after the drug is stopped, and the skin irritation of times of administration of the calcitriol patch is judged according to the irritation symptom scoring standard and the irritation strength judging standard.
The irritation symptom scoring standard is mainly used for observing whether erythema and edema exist on the skin of the administration position of the depilatory area.
| Erythema condition | No erythema | Slight erythema | Moderate erythema | Severe erythema | Severe erythema and eschar |
| Edema condition | Without edema | Mild edema | Clear outline of edema | / | Edema with 1mm swelling2 |
| Score of | 0 point (min) | 1 minute (1) | 2 is divided into | 3 points of | 4 is divided into |
Calculating average reaction score of each group of animals and normal saline, and judging skin irritation intensity according to the average reaction score
| Intensity of irritation | l is non-irritant | Mild irritation | Moderate irritation | Strong irritation Property |
| Average reaction score | l 0.5 | l 0.5~3.0 | l 3.0~6.0 | l 6.0 |
The results of the skin irritation tests of examples 1-4 are shown in Table 4. The results show that the calcitriol patches and the normal saline prepared in examples 1-4 have average reaction scores of less than 0.5 to the intact skin group, indicating that both are non-irritating to intact skin; the mean reaction scores of the calcitriol patch and the normal saline prepared in examples 1-4 on the damaged skin group were 0.5-3.0 in 1h and 24h after drug withdrawal, which indicates that the calcitriol patch and the normal saline have slight irritation on the damaged skin, but the calcitriol patch and the normal saline disappear automatically and have no irritation in 48h after drug withdrawal.
TABLE 4 results of skin irritation test of calcitriol patches prepared in examples 1-4
Claims (4)
1. The calcitriol patch is composed of a back lining layer, a drug storage layer and an anti-adhesion layer, and is characterized in that the drug storage layer comprises calcitriol, a pressure-sensitive adhesive and a percutaneous absorption promoter, wherein the calcitriol accounts for 0.010-0.032% of the solid content of the pressure-sensitive adhesive, the percutaneous absorption promoter accounts for 1.0-20.0% of the solid content of the pressure-sensitive adhesive, the matrix material selected by the pressure-sensitive adhesive is or more compounds of silicone polymers, isobutylene polymers, acrylate polymers or cellulose, and the percutaneous absorption promoter is or more of sulfoxides, pyrrolidones, laurocapram, fatty acids and esters thereof, surfactants, alcohols, polyols, terpenes, amines, amides, cyclodextrins and phospholipids.
2. The calcitriol patch according to claim 1, wherein or more of inert filler, plasticizer, tackifier or antioxidant is added, and the dosage of the or more is 0% -10% of the solid content of the pressure sensitive adhesive.
3. Calcitriol patch according to claim 1, characterized in that: the back lining layer is made of aluminum-containing polyethylene composite film or elastic non-woven fabric; the anti-sticking layer is a polyester film or paper with the surface treated by silicon oil anti-sticking treatment or containing fluorine.
4. The preparation process of calcitriol patch according to claim 1, wherein the calcitriol patch is prepared by mixing calcitriol, pressure sensitive adhesive and percutaneous absorption enhancer, coating on the anti-sticking layer, drying at 40-80 deg.C, compounding with aluminum-containing polyethylene composite film or elastic non-woven back layer, and cutting into pieces with certain size and specification.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810787794.9A CN110731952A (en) | 2018-07-18 | 2018-07-18 | calcitriol patch and its preparation method |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810787794.9A CN110731952A (en) | 2018-07-18 | 2018-07-18 | calcitriol patch and its preparation method |
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| CN110731952A true CN110731952A (en) | 2020-01-31 |
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| CN201810787794.9A Pending CN110731952A (en) | 2018-07-18 | 2018-07-18 | calcitriol patch and its preparation method |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111494321A (en) * | 2020-04-28 | 2020-08-07 | 南通华山药业有限公司 | Calcitriol long-circulating liposome and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004028515A1 (en) * | 2002-09-26 | 2004-04-08 | Young-Kweon Choi | Matrix type patch for transdermal administration of vitamin d analog and the use thereof |
| US20180169034A1 (en) * | 2015-06-14 | 2018-06-21 | Trs Ii, Llc | Transdermal delivery formulation |
-
2018
- 2018-07-18 CN CN201810787794.9A patent/CN110731952A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004028515A1 (en) * | 2002-09-26 | 2004-04-08 | Young-Kweon Choi | Matrix type patch for transdermal administration of vitamin d analog and the use thereof |
| US20180169034A1 (en) * | 2015-06-14 | 2018-06-21 | Trs Ii, Llc | Transdermal delivery formulation |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111494321A (en) * | 2020-04-28 | 2020-08-07 | 南通华山药业有限公司 | Calcitriol long-circulating liposome and preparation method thereof |
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Application publication date: 20200131 |