CN115778924A - Loratadine preparation and preparation method thereof - Google Patents
Loratadine preparation and preparation method thereof Download PDFInfo
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- CN115778924A CN115778924A CN202211659586.3A CN202211659586A CN115778924A CN 115778924 A CN115778924 A CN 115778924A CN 202211659586 A CN202211659586 A CN 202211659586A CN 115778924 A CN115778924 A CN 115778924A
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Abstract
The invention provides a loratadine preparation and a preparation method thereof. A preparation method of the loratadine preparation comprises the following steps: dissolving with toluene, adding ethyl chloroformate for reaction, adding water to separate out a benzene layer, processing the intermediate II, processing oily substances, dissolving, pulping, drying and preparing a membrane. The loratadine and other auxiliary materials are added with water to prepare the slurry, the slurry is coated on the patch to prepare the loratadine film-shaped preparation, the loratadine film-shaped preparation has two functions of oral administration and external application, when the loratadine film-shaped preparation is orally taken, the film-shaped preparation is taken out of the patch and is dissolved on the tongue, when the loratadine film-shaped preparation is externally applied, the patch is pasted on an affected part, and if the effective time of the loratadine is required to be shortened, a little water is sprayed on the outer side of the patch to dissolve the film-shaped preparation, so that the loratadine film-shaped preparation has wider applicability, convenience is brought to patients, the requirements of different consumers are met, and the waste of medicines can be effectively reduced.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a loratadine preparation and a preparation method thereof.
Background
Loratadine, developed by Schering-plough company and marketed in belgium in 1988, is a long-acting tricyclic antihistamine clinically used for alleviating symptoms associated with allergic rhinitis, such as sneezing, watery nasal discharge and nasal itching, and ocular itching and burning sensation, and also for alleviating symptoms of chronic urticaria and other allergic skin diseases, and has a stronger selectivity in its action against peripheral H receptors than other antihistamines, and thus, the therapeutic effect is more remarkable.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide a loratadine preparation and a preparation method thereof.
A preparation method of loratadine preparation comprises the following steps:
s1: dissolving with toluene
Adding 4- (8-chloro-5,6-diammine-11H-benzo [5,6] cyclohepta [1,2-b ] pyridine-11-subunit) -1-methylpiperidine and toluene into a stirrer together, stirring for 1-2H at the stirring speed of 100-200r/min, and uniformly mixing to obtain a mixed solution;
s2: adding ethyl chloroformate for reaction
Pressing the heated ethyl chloroformate into the mixed solution through a guide pipe, and stirring the ethyl chloroformate and the mixed solution simultaneously to obtain an intermediate I;
s3: adding water to separate out benzene layer
Adding the intermediate I and water into a delayer according to a volume ratio of 1:1-3, carrying out delamination, and taking out a benzene layer to obtain an intermediate II;
s4: treatment of intermediate II
Washing the intermediate II with water, drying, and concentrating under reduced pressure to obtain an oily substance;
s5: treatment of oils
Adding the oily matter into ether for dipping, and then recrystallizing to obtain loratadine;
s6: dissolving pulping and drying film preparation
Adding loratadine and auxiliary materials into water, stirring uniformly to obtain slurry I, adding a penetration enhancer to obtain slurry II, coating the slurry II into a patch, ultrasonically degassing, heating and pressurizing to obtain a loratadine film-shaped preparation.
Further, the step S2 specifically includes the following steps:
s2.1: adding ethyl chloroformate into a liquid storage tank;
s2.2: starting a heater on the liquid storage tank, heating ethyl chloroformate to 50-60 ℃, and then preserving heat;
s2.3: and (3) starting a pressure pump on the liquid storage tank, pressing ethyl chloroformate into the mixed liquid prepared in the step (S1) from the small hole on the inner wall of the stirrer through a guide pipe, and continuously stirring for 45-60 min to react the ethyl chloroformate with the mixed liquid to obtain an intermediate I.
Further, the step S6 specifically includes the following steps:
s6.1: adding loratadine and auxiliary materials into water according to the mass ratio of 1-2:1, and stirring for 3-5 hours to prepare slurry I;
s6.2: adding a penetration enhancer into the slurry I, continuously stirring for 1-2h, and then standing for 5-6h to obtain slurry II;
s6.3: and uniformly coating the slurry II in the groove of the patch, then putting the patch into an ultrasonic degasser, heating and drying the slurry II on the patch by using a heating plate, and pressurizing the slurry II on the patch by using a pressurizing air pump to obtain the loratadine film-shaped preparation.
Further, the auxiliary materials comprise a water-soluble polymer film-forming material, a plasticizer and a stabilizer, wherein the water-soluble polymer film-forming material comprises two or more of polyvinyl alcohol, hydroxypropyl cellulose, sodium alginate, bletilla hyacinthine gum, maltodextrin and corn starch; the plasticizer comprises more than one of polyethylene glycol, glycerol or tween 80; the stabilizer is one of sodium sulfite, sodium bisulfite and vitamin E.
Further, the penetration enhancer comprises oleic acid, menthoic acid, azone and phospholipid, and the volume fraction ratio of the four is 10-15.
Furthermore, the paster is a water-permeable release paper, and the groove on the paster is enclosed by the rubber ring.
Further, the temperature of the heating plate is kept between 50 ℃ and 100 ℃, and the slurry in the patch is dried for 2 hours to 4 hours.
Further, the pressurizing air pump pressurizes the inside of the ultrasonic degasser, so that the air pressure is kept between 200 and 300kPa.
Further, a loratadine preparation prepared by the preparation method of the loratadine preparation.
Compared with the prior art, the invention has the advantages and beneficial effects that:
1. the loratadine and other auxiliary materials are added with water to prepare the slurry, and the slurry is coated on the patch to prepare the loratadine film-shaped preparation, so that the loratadine film-shaped preparation has two functions of oral administration and external application.
2. The invention heats the ethyl chloroformate and presses the ethyl chloroformate into the mixed liquor from the small holes on the inner wall of the stirrer, so that the ethyl chloroformate can react with the mixed liquor more quickly and fully, and the preparation time is effectively saved.
3. According to the invention, the temperature of the patch is raised while ultrasonic degassing is carried out, so that the slurry on the patch can be dried into the membrane-shaped body, the preparation time is saved, and the membrane-shaped body can be more smoothly and flatly attached to the patch by pressurizing at the same time.
Drawings
Fig. 1 is a flow chart of a method of preparing a loratadine formulation employed in an embodiment of the present invention.
Detailed Description
The present invention will be described in further detail with reference to specific examples.
Example 1
A method for preparing a loratadine preparation, as shown in fig. 1, comprising the following steps:
s1: dissolving with toluene
Adding 4- (8-chloro-5,6-diammine-11H-benzo [5,6] cyclohepta [1,2-b ] pyridine-11-subunit) -1-methylpiperidine and toluene into a stirrer together, stirring for 1H at the stirring speed of 100r/min, and uniformly mixing to obtain a mixed solution;
s2: adding ethyl chloroformate for reaction
Adding ethyl chloroformate into a liquid storage tank, starting a heater on the liquid storage tank to heat the ethyl chloroformate to 60 ℃, then preserving heat, communicating the liquid storage tank with a stirrer through a guide pipe, uniformly forming compact small holes in the inner wall of the joint of the stirrer and the guide pipe, and further arranging a one-way valve at the inner wall, starting a pressure pump on the liquid storage tank, pressing the ethyl chloroformate into the mixed solution prepared by S1 through the small holes in the inner wall of the stirrer through the guide pipe, continuing stirring for 45min at the same time, reacting the ethyl chloroformate with the mixed solution to obtain an intermediate I, heating the ethyl chloroformate and pressing the ethyl chloroformate into the mixed solution through the small holes in the inner wall of the stirrer, so that the ethyl chloroformate can react with the mixed solution more quickly and fully, and the preparation time is effectively saved;
s3: adding water to separate out benzene layer
Adding the intermediate I and water into a delayer according to the volume ratio of 1:1, carrying out delamination, and taking out a benzene layer to obtain an intermediate II;
s4: treatment of intermediate II
Washing the intermediate II with water, drying, and concentrating under reduced pressure to obtain oily substance;
s5: treatment of oils
Adding the oily matter into ether for dipping, and then recrystallizing to obtain loratadine;
s6: dissolving pulping and drying film
The preparation method comprises the following steps of (1): 1 adding water, and adding auxiliary materials including a water-soluble high-molecular film forming material, a plasticizer and a stabilizer, wherein the water-soluble high-molecular film forming material comprises two or more of polyvinyl alcohol, hydroxypropyl cellulose, sodium alginate, bletilla hyacinthine gum, maltodextrin and corn starch; the plasticizer comprises more than one of polyethylene glycol, glycerol or tween 80; the stabilizer is one of sodium sulfite, sodium bisulfite and vitamin E, then stirring is carried out for 5 hours to prepare a slurry I, a permeation enhancer is added into the slurry I, the permeation enhancer comprises oleic acid, menthoic acid, azone and phospholipid, the volume fraction ratio of the four components is 10.
Example 2
A method for preparing a loratadine preparation, as shown in fig. 1, comprising the following steps:
s1: dissolving with toluene
Adding 4- (8-chloro-5,6-diammine-11H-benzo [5,6] cyclohepta [1,2-b ] pyridine-11-subunit) -1-methylpiperidine and toluene into a stirrer together, stirring for 2 hours at the stirring speed of 200r/min, and uniformly mixing to obtain a mixed solution;
s2: adding ethyl chloroformate for reaction
Adding ethyl chloroformate into a liquid storage tank, starting a heater on the liquid storage tank to heat the ethyl chloroformate to 55 ℃, then preserving heat, communicating the liquid storage tank with a stirrer through a guide pipe, uniformly forming compact small holes in the inner wall of the joint of the stirrer and the guide pipe, and further arranging a one-way valve at the inner wall, starting a pressure pump on the liquid storage tank, pressing the ethyl chloroformate into the mixed solution prepared by S1 through the small holes in the inner wall of the stirrer through the guide pipe, continuing stirring for 45min at the same time, reacting the ethyl chloroformate with the mixed solution to obtain an intermediate I, heating the ethyl chloroformate and pressing the ethyl chloroformate into the mixed solution through the small holes in the inner wall of the stirrer, so that the ethyl chloroformate can react with the mixed solution more quickly and fully, and the preparation time is effectively saved;
s3: adding water to separate out benzene layer
Adding the intermediate I and water into a delayer according to the volume ratio of 1:1, carrying out delamination, and taking out a benzene layer to obtain an intermediate II;
s4: treatment of intermediate II
Washing the intermediate II with water, drying, and concentrating under reduced pressure to obtain an oily substance;
s5: treatment of oils
Adding the oily matter into ether for dipping, and then recrystallizing to obtain loratadine;
s6: dissolving pulping and drying film
Adding loratadine and auxiliary materials into water according to a mass ratio of 2:1, wherein the auxiliary materials comprise water-soluble high-molecular film-forming materials, plasticizers and stabilizers, and the water-soluble high-molecular film-forming materials comprise two or more of polyvinyl alcohol, hydroxypropyl cellulose, sodium alginate, bletilla hyacinthine gum, maltodextrin and corn starch; the plasticizer comprises more than one of polyethylene glycol, glycerol or tween 80; the stabilizer is one of sodium sulfite, sodium bisulfite and vitamin E, then stir 5h, make slurry I, add penetration enhancer to slurry I, penetration enhancer includes oleic acid, mentha acid, azone and phosphatide, and the volume fraction ratio of four is 12.
Example 3
A method for preparing a loratadine preparation, as shown in fig. 1, comprising the following steps:
s1: dissolving with toluene
Adding 4- (8-chloro-5,6-diammine-11H-benzo [5,6] cyclohepta [1,2-b ] pyridine-11-subunit) -1-methylpiperidine and toluene into a stirrer together, stirring for 1H at the stirring speed of 100r/min, and uniformly mixing to obtain a mixed solution;
s2: adding ethyl chloroformate for reaction
Adding ethyl chloroformate into a liquid storage tank, starting a heater on the liquid storage tank, keeping the temperature when the ethyl chloroformate is heated to 60 ℃, communicating the liquid storage tank with a stirrer through a guide pipe, uniformly forming compact small holes in the inner wall of the joint of the stirrer and the guide pipe, and further arranging a one-way valve, starting a pressure pump on the liquid storage tank, pressing the ethyl chloroformate into the mixed solution prepared by S1 from the small holes in the inner wall of the stirrer through the guide pipe, continuously stirring for 60min, reacting the ethyl chloroformate with the mixed solution to obtain an intermediate I, heating the ethyl chloroformate and pressing the ethyl chloroformate into the mixed solution from the small holes in the inner wall of the stirrer, so that the ethyl chloroformate can react with the mixed solution more quickly and fully, and the preparation time is effectively saved;
s3: adding water to separate out benzene layer
Adding the intermediate I and water into a delayer according to the volume ratio of 1:2, carrying out delamination, and taking out a benzene layer to obtain an intermediate II;
s4: treatment of intermediate II
Washing the intermediate II with water, drying, and concentrating under reduced pressure to obtain oily substance;
s5: treatment of oils
Adding the oily matter into ether for dipping, and then recrystallizing to obtain loratadine;
s6: dissolving pulping and drying film
Adding loratadine and auxiliary materials into water according to a mass ratio of 1:1, wherein the auxiliary materials comprise water-soluble high-molecular film-forming materials, plasticizers and stabilizers, and the water-soluble high-molecular film-forming materials comprise two or more of polyvinyl alcohol, hydroxypropyl cellulose, sodium alginate, bletilla hyacinthine gum, maltodextrin and corn starch; the plasticizer comprises more than one of polyethylene glycol, glycerol or tween 80; the stabilizer is one of sodium sulfite, sodium bisulfite and vitamin E, then stir 4h, make slurry I, add penetration enhancer to slurry I, penetration enhancer includes oleic acid, mentha acid, azone and phosphatide, and the volume fraction ratio of four is 10.
The foregoing embodiments are merely illustrative of the principles and utilities of the present invention and are not intended to limit the invention. Any person skilled in the art can modify or change the above-mentioned embodiments without departing from the spirit and scope of the present invention. Accordingly, it is intended that all equivalent modifications or changes which can be made by those skilled in the art without departing from the spirit and technical spirit of the present invention be covered by the claims of the present invention.
Claims (9)
1. A preparation method of a loratadine preparation is characterized by comprising the following steps:
s1: dissolving with toluene
Adding 4- (8-chloro-5,6-diammine-11H-benzo [5,6] cyclohepta [1,2-b ] pyridine-11-subunit) -1-methylpiperidine and toluene into a stirrer together, stirring for 1-2H at the stirring speed of 100-200r/min, and uniformly mixing to obtain a mixed solution;
s2: adding ethyl chloroformate for reaction
Pressing the heated ethyl chloroformate into the mixed solution through a guide pipe, and stirring simultaneously to obtain an intermediate I after the two react;
s3: adding water to separate out benzene layer
Adding the intermediate I and water into a delayer according to the volume ratio of 1:1-3, delaminating, and taking out a benzene layer to obtain an intermediate II;
s4: treatment of intermediate II
Washing the intermediate II with water, drying, and concentrating under reduced pressure to obtain an oily substance;
s5: treatment of oils
Adding the oily matter into ether for dipping, and then recrystallizing to obtain loratadine;
s6: dissolving pulping and drying film
Adding loratadine and auxiliary materials into water, stirring uniformly to obtain slurry I, adding a penetration enhancer to obtain slurry II, coating the slurry II into a patch, ultrasonically degassing, heating and pressurizing to obtain a loratadine film-shaped preparation.
2. The method for preparing loratadine according to claim 1, wherein the step S2 of adding ethyl chloroformate for reaction comprises the following steps:
s2.1: adding ethyl chloroformate into a liquid storage tank;
s2.2: starting a heater on the liquid storage tank, heating ethyl chloroformate to 50-60 ℃, and then preserving heat;
s2.3: and (3) starting a pressure pump on the liquid storage tank, pressing ethyl chloroformate into the mixed liquid prepared in the step (S1) from the small hole on the inner wall of the stirrer through a guide pipe, and continuously stirring for 45-60 min to react the ethyl chloroformate with the mixed liquid to obtain an intermediate I.
3. The method for preparing a loratadine preparation according to claim 1, wherein the dissolving, pulping, drying and film-making of step S6 specifically comprises the following steps:
s6.1: adding loratadine and auxiliary materials into water according to the mass ratio of 1-2:1, and stirring for 3-5 hours to prepare slurry I;
s6.2: adding a penetration enhancer into the slurry I, continuously stirring for 1-2h, and standing for 5-6h to obtain slurry II;
s6.3: and uniformly coating the slurry II in the groove of the patch, then putting the patch into an ultrasonic degasser, heating and drying the slurry II on the patch by using a heating plate, and pressurizing the slurry II on the patch by using a pressurizing air pump to obtain the loratadine film-shaped preparation.
4. The method for preparing loratadine preparation according to claim 3, wherein the auxiliary materials comprise water-soluble polymer film-forming material, plasticizer and stabilizer, wherein the water-soluble polymer film-forming material comprises two or more of polyvinyl alcohol, hydroxypropyl cellulose, sodium alginate, bletilla hyacinthine gum, maltodextrin and corn starch; the plasticizer comprises more than one of polyethylene glycol, glycerol or tween 80;
the stabilizer is one of sodium sulfite, sodium bisulfite and vitamin E.
5. The method for preparing a loratadine preparation according to claim 3, wherein the penetration enhancer comprises oleic acid, menthoic acid, azone and phospholipid, and the volume fraction ratio of the four is 10-15.
6. A method of preparing a loratadine formulation according to claim 3 wherein the patch is a water permeable release paper and the recess in the patch is surrounded by a rubber ring.
7. The method for preparing loratadine preparation according to claim 3 wherein the temperature of the hot plate is maintained between 50-100 ℃, and the slurry in the patch is dried for 2-4h.
8. The method of claim 3, wherein the inside of the ultrasonic degasifier is pressurized by the pressurizing air pump so that the pressure of the air is maintained at 200 to 300kPa.
9. A loratadine formulation prepared by the process of any of claims 1-8, wherein the loratadine formulation is a loratadine formulation.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202211659586.3A CN115778924A (en) | 2022-12-22 | 2022-12-22 | Loratadine preparation and preparation method thereof |
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| CN202211659586.3A CN115778924A (en) | 2022-12-22 | 2022-12-22 | Loratadine preparation and preparation method thereof |
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| CN202211659586.3A Pending CN115778924A (en) | 2022-12-22 | 2022-12-22 | Loratadine preparation and preparation method thereof |
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Citations (5)
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|---|---|---|---|---|
| US4282233A (en) * | 1980-06-19 | 1981-08-04 | Schering Corporation | Antihistaminic 11-(4-piperidylidene)-5H-benzo-[5,6]-cyclohepta-[1,2-b]-pyridines |
| CN1599736A (en) * | 2001-11-05 | 2005-03-23 | 萨宝集团公司 | Process for the preparation of 4-(8-chloro-5,6-dihydro-11h-benzo(5,6)-cyclohepta-(1,2b)-pyridin-11-ylidene)-1-piperidinecarboxyli c acid ethyl ester (loratadine) |
| CN1600297A (en) * | 2003-09-23 | 2005-03-30 | 中国医学科学院药物研究所 | Loratadine paster of penetrating skin |
| US20140256765A1 (en) * | 2013-03-11 | 2014-09-11 | Pharmaceutical Productions Inc. | Transmucosal drug delivery system |
| US20190358172A1 (en) * | 2017-08-10 | 2019-11-28 | Avro Life Sciences, Inc. | Transdermal Drug Delivery System |
-
2022
- 2022-12-22 CN CN202211659586.3A patent/CN115778924A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4282233A (en) * | 1980-06-19 | 1981-08-04 | Schering Corporation | Antihistaminic 11-(4-piperidylidene)-5H-benzo-[5,6]-cyclohepta-[1,2-b]-pyridines |
| US4282233B1 (en) * | 1980-06-19 | 2000-09-05 | Schering Corp | Antihistaminic 11-(4-piperidylidene)-5h-benzoÄ5,6Ü-cyclohepta-Ä1,2Ü-pyridines |
| CN1599736A (en) * | 2001-11-05 | 2005-03-23 | 萨宝集团公司 | Process for the preparation of 4-(8-chloro-5,6-dihydro-11h-benzo(5,6)-cyclohepta-(1,2b)-pyridin-11-ylidene)-1-piperidinecarboxyli c acid ethyl ester (loratadine) |
| CN1600297A (en) * | 2003-09-23 | 2005-03-30 | 中国医学科学院药物研究所 | Loratadine paster of penetrating skin |
| US20140256765A1 (en) * | 2013-03-11 | 2014-09-11 | Pharmaceutical Productions Inc. | Transmucosal drug delivery system |
| US20190358172A1 (en) * | 2017-08-10 | 2019-11-28 | Avro Life Sciences, Inc. | Transdermal Drug Delivery System |
Non-Patent Citations (1)
| Title |
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