CN113893357A - Desloratadine preparation and preparation method thereof - Google Patents
Desloratadine preparation and preparation method thereof Download PDFInfo
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- CN113893357A CN113893357A CN202111430923.7A CN202111430923A CN113893357A CN 113893357 A CN113893357 A CN 113893357A CN 202111430923 A CN202111430923 A CN 202111430923A CN 113893357 A CN113893357 A CN 113893357A
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- desloratadine
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Images
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pulmonology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Otolaryngology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Immunology (AREA)
Abstract
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a desloratadine preparation and a preparation method thereof. The desloratadine and the carrier material are combined through intermolecular force to form a supramolecular compound, so that the problem of poor water solubility of the desloratadine is solved, the content of related substances is reduced, and the stability of the desloratadine is improved. According to the invention, the preparation method is optimized by optimizing the types and the proportion of the loratadine and the drug-loaded material, so that the drug-loaded amount of the loratadine is increased, the clinical application dose is reduced, and the clinical requirement is more easily met.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a desloratadine preparation and a preparation method thereof.
Background
Desloratadine is a non-sedating long-acting tricyclic antihistamine, is an active metabolite of the loratadine, can selectively antagonize peripheral H1 receptors, has similar pharmacological action to the loratadine, but has stronger effect and quicker response time, and can relieve the related symptoms of seasonal allergic rhinitis or chronic idiopathic urticaria. However, desloratadine has encountered great difficulty in formulation due to its well-known instability and low water solubility.
Chinese patent CN1268377A discloses a desloratadine dry suspension and a preparation method thereof, wherein a desloratadine raw material is coated and then mixed with other auxiliary materials to prepare the dry suspension, so that the stability of the desloratadine is improved, but the dry suspension is complex in process and difficult to produce.
Several approaches to addressing the instability of desloratadine formulations are disclosed in US2002/123504 including: firstly, using anhydrous land or non-hygroscopic loratadine raw material; increasing the particle size of desloratadine; protecting and isolating the coating of the desloratadine raw material; and fourthly, avoiding using acid auxiliary materials, lactose and other auxiliary materials to avoid mallard reaction.
At present, the problems that the desloratadine is difficult to dissolve in water and the stability is difficult to control are not well solved. In order to overcome the defects of the prior art, the problem of poor solubility is solved, and a desloratadine preparation with high stability is developed.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention provides a desloratadine preparation with high stability, the problem of low water solubility of the desloratadine is solved by combining the desloratadine with a macrocyclic compound, the stability of the preparation is improved, the preparation process is simple and easy to control, and animal experiments show that the treatment effect on allergic rhinitis is obviously improved.
Specifically, the technical scheme of the invention is as follows:
the invention provides a desloratadine preparation which comprises desloratadine, a carrier material and pharmaceutically acceptable auxiliary materials.
The desloratadine is used as a drug guest molecule, the carrier material is used as a host molecule, and a supramolecular compound is formed by combination of intermolecular forces, wherein the intermolecular forces include but are not limited to coordination bonds, hydrogen bonds, pi-pi stacking effect, electrostatic effect, hydrophobic effect and the like.
Further, the dosage of the loratadine and the carrier material is 1-5 by mole ratio: 1.
further, the carrier material is a macrocyclic compound with a cavity or a pore channel, including but not limited to DNA, crown ether, cyclodextrin, calixarene, calixazole, cucurbituril, pillared arene, and the like.
Specifically, the macrocyclic compound is cucurbituril, and the cucurbituril comprises cucurbit [5] urea, cucurbit [6] urea, cucurbit [7] urea, cucurbit [8] urea, cucurbit [10] urea and cucurbit [14] urea, and preferably cucurbit [7] urea.
Further, the loratadine and the carrier material are combined to form a supramolecular compound in a molar ratio of 1:1 or/and 2:1, as exemplified in FIG. 1, amino groups in the desloratadine are combined with oxygen atoms inside cucurbit [7] urea in a hydrogen bond mode to form the supramolecular compound, and the cucurbit [7] urea can carry the loratadine in a molar ratio of 1:1 or/and 2:1 through an N-H.O.hydrogen bond.
Furthermore, the supramolecular compound also comprises water molecules and/or solvent molecules, and the water molecules and/or solvent molecules exist in the supramolecular compound in a hydrogen bond mode, a pi-pi stacking effect mode, an electrostatic effect mode, a hydrophobic effect mode and the like.
Further, the supramolecular compound can be prepared into a preparation with pharmaceutically acceptable auxiliary materials, wherein the preparation comprises but is not limited to tablets, capsules, granules, pills, suspensions, ointments, emulsions and aerosols; the auxiliary materials include but are not limited to fillers, disintegrants, lubricants, binders, stabilizers and flavoring agents.
The second purpose of the invention is to provide a method for preparing the desloratadine preparation, which comprises the following steps:
(1) preparation of desloratadine supramolecular compounds: dissolving desloratadine and a carrier material in a solvent respectively, mixing, carrying out rotary evaporation for 1-3h under reduced pressure to obtain an emulsion, and carrying out vacuum drying to obtain the desloratadine-containing emulsion;
(2) adding pharmaceutically acceptable auxiliary materials into the desloratadine supramolecular compound obtained in the step (1), and preparing the preparation according to a conventional method.
Further, the step (1) is as follows: dissolving desloratadine in one of methanol, ethanol, propylene glycol and water, and dissolving the desloratadine in the solvent by ultrasonic waves to obtain a solution A; dissolving a carrier material in water, and dissolving the carrier material by ultrasonic to obtain a solution B; slowly mixing the solution A and the solution B, heating in a water bath kettle, reducing pressure, steaming, gradually increasing the heating temperature from 25 deg.C to 40 deg.C for 1-3 hr to obtain emulsion, and vacuum drying under reduced pressure.
Specifically, the solvent is preferably ethanol, and the heating temperature is gradually increased from 25 ℃ to 40 ℃ and is gradually adjusted according to the flow rate of the distillate, and is increased by 3-5 ℃ each time until the temperature reaches 40 ℃.
Compared with the prior art, the invention has the beneficial effects that:
(1) the invention combines the desloratadine with macrocyclic compound, especially cucurbit [7] uril to form supermolecule compound, solves the problem of poor water solubility of the desloratadine, reduces the content of related substances, and improves the stability of the desloratadine.
(2) The preparation method of the desloratadine supramolecular compound is simple and high in yield; the preparation method is optimized by optimizing the types and the proportion of the loratadine and the drug-loaded material, so that the drug-loaded amount of the loratadine is improved, the clinical application dose is reduced, and the clinical requirement is more easily met.
(3) Rat experiments prove that the traditional Chinese medicine can obviously relieve symptoms such as rhinocnesmus, rhinorrhea, sneeze and the like caused by allergic rhinitis; the content levels of IL-2, IL-4, Ig E and ECP in the serum of a model rat are reduced, and the effect of treating allergic rhinitis is better than that of a commercial preparation.
Drawings
FIG. 1: structural schematic diagram of desloratadine-cucurbit [7] urea supramolecular compound: (a) the molar ratio is 1: 1; (b) the molar ratio is 2: 1.
Detailed Description
In order to make the purpose and technical solution of the present invention more clear, the present invention is further described with reference to the following examples, but the scope of the present invention is not limited to these examples, and the examples are only used for explaining the present invention. It will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true scope of the invention.
Examples 1-4 Desloratadine supramolecular Compounds
The preparation method comprises the following steps:
the molar ratio of desloratadine to cucurbituril is 2: 1.
Dissolving desloratadine in 100ml of ethanol, and dissolving the desloratadine by ultrasonic waves to obtain a solution A; dissolving cucurbituril in 200ml of water, and performing ultrasonic dissolution to obtain a solution B; slowly mixing solution A and solution B, heating at 25 deg.C, depressurizing, rotary distilling, observing flow rate of distillate, increasing water bath temperature to 40 deg.C gradually when flow rate is reduced or no longer distilled, increasing temperature by 3-5 deg.C each time, obtaining emulsion after 1-3 hr, and vacuum drying under reduced pressure.
Examples 5-9 Desloratadine supramolecular Compounds
The preparation method comprises the following steps:
example 5: the molar ratio of desloratadine to cucurbituril is 1: 1.
Example 6: the molar ratio of desloratadine to cucurbituril is 2: 1.
Example 7: the molar ratio of desloratadine to cucurbituril is 3: 1.
Example 8: the molar ratio of desloratadine to cucurbituril is 4: 1.
Example 9: the molar ratio of desloratadine to cucurbituril is 5: 1.
Dissolving desloratadine in 100ml of ethanol, and dissolving the desloratadine by ultrasonic waves to obtain a solution A; dissolving cucurbit [7] uril in 100-500ml of water (adjusted according to the dosage of cucurbit [7] uril), and performing ultrasonic dissolution to obtain a solution B; slowly mixing solution A and solution B, heating at 25 deg.C, depressurizing, rotary distilling, observing flow rate of distillate, increasing water bath temperature to 40 deg.C gradually when flow rate is reduced or no longer distilled, increasing temperature by 3-5 deg.C each time, obtaining emulsion after 1-3 hr, and vacuum drying under reduced pressure.
Examples 10-13 Desloratadine supramolecular Compounds
The preparation method comprises the following steps:
examples 10 to 11: the molar ratio of desloratadine to cucurbituril is 1: 1.
Examples 12 to 13: the molar ratio of desloratadine to cucurbituril is 2: 1.
Dissolving desloratadine in 10-200ml of ethanol (adjusted according to the dosage of the desloratadine), and dissolving the desloratadine by ultrasonic waves to obtain a solution A; dissolving cucurbit [7] uril in 10-1000ml of water (adjusted according to the dosage of cucurbit [7] uril), and performing ultrasonic dissolution to obtain a solution B; slowly mixing solution A and solution B, heating at 25 deg.C, depressurizing, rotary distilling, observing flow rate of distillate, increasing water bath temperature to 40 deg.C gradually when flow rate is reduced or no longer distilled, increasing temperature by 3-5 deg.C each time, obtaining emulsion after 1-3 hr, and vacuum drying under reduced pressure.
Examples 14-16 Desloratadine supramolecular Compounds
Example 14 preparation method:
dissolving desloratadine in 50ml of methanol, and dissolving the desloratadine by ultrasonic waves to obtain a solution A; dissolving cucurbit [7] uril in 200ml of water, and dissolving by ultrasonic to obtain a solution B; slowly mixing solution A and solution B, heating at 25 deg.C, depressurizing, rotary distilling, observing flow rate of distillate, increasing water bath temperature to 40 deg.C gradually when flow rate is reduced or no longer distilled, increasing temperature by 3-5 deg.C each time, obtaining emulsion after 1-3 hr, and vacuum drying under reduced pressure.
Example 15 preparation method:
dissolving desloratadine in 50ml of propylene glycol, and dissolving the desloratadine by ultrasonic waves to obtain a solution A; dissolving cucurbit [7] uril in 200ml of water, and dissolving by ultrasonic to obtain a solution B; slowly mixing solution A and solution B, heating at 25 deg.C, depressurizing, rotary distilling, observing flow rate of distillate, increasing water bath temperature to 40 deg.C gradually when flow rate is reduced or no longer distilled, increasing temperature by 3-5 deg.C each time, obtaining emulsion after 1-3 hr, and vacuum drying under reduced pressure.
Example 16 preparation method:
dissolving desloratadine in 100ml of water, and dissolving the desloratadine by ultrasonic waves to obtain a solution A; dissolving cucurbit [7] uril in 200ml of water, and dissolving by ultrasonic to obtain a solution B; slowly mixing solution A and solution B, heating at 25 deg.C, depressurizing, rotary distilling, observing flow rate of distillate, increasing water bath temperature to 40 deg.C gradually when flow rate is reduced or no longer distilled, increasing temperature by 3-5 deg.C each time, obtaining emulsion after 1-3 hr, and vacuum drying under reduced pressure.
EXAMPLE 17 Desloratadine tablets (400 tablets)
The preparation method comprises the following steps:
dissolving desloratadine in 100ml of ethanol, and dissolving the desloratadine by ultrasonic waves to obtain a solution A; dissolving cucurbituril in 200ml of water, and performing ultrasonic dissolution to obtain a solution B; slowly mixing the solution A and the solution B, placing the mixture in a water bath kettle, heating at 25 ℃, decompressing and carrying out rotary distillation, observing the flow rate of a distillate, increasing the water bath temperature to gradually increase the temperature to 40 ℃ when the flow rate is reduced or is not distilled, increasing the temperature by 3-5 ℃ each time, obtaining an emulsion after 1-3h, and drying under vacuum reduced pressure to obtain desloratadine-cucurbit [7] urea supramolecular compound powder; pulverizing 10g of the above powder, sieving, adding microcrystalline cellulose 75g (filler) and sodium alginate 5g (binder), sieving, and making into tablet by dry granulation and tabletting method.
Example 18 Desloratadine granules (400 parts)
The preparation method comprises the following steps:
dissolving desloratadine in 100ml of ethanol, and dissolving the desloratadine by ultrasonic waves to obtain a solution A; dissolving cucurbituril in 200ml of water, and performing ultrasonic dissolution to obtain a solution B; slowly mixing the solution A and the solution B, placing the mixture in a water bath kettle, heating at 25 ℃, decompressing and carrying out rotary distillation, observing the flow rate of a distillate, increasing the water bath temperature to gradually increase the temperature to 40 ℃ when the flow rate is reduced or is not distilled, increasing the temperature by 3-5 ℃ each time, obtaining an emulsion after 1-3h, and drying under vacuum reduced pressure to obtain desloratadine-cucurbit [7] urea supramolecular compound powder; taking 10g of the powder, crushing and sieving, adding 70g of mannitol (filler), 5g of povidone (adhesive) and 5g of dry starch (disintegrant), sieving, granulating, drying and finishing to obtain the finished product.
EXAMPLE 19 Desloratadine capsules (400 capsules)
The preparation method comprises the following steps:
dissolving desloratadine in 100ml of ethanol, and dissolving the desloratadine by ultrasonic waves to obtain a solution A; dissolving cucurbituril in 200ml of water, and performing ultrasonic dissolution to obtain a solution B; slowly mixing the solution A and the solution B, placing the mixture in a water bath kettle, heating at 25 ℃, decompressing and carrying out rotary distillation, observing the flow rate of a distillate, increasing the water bath temperature to gradually increase the temperature to 40 ℃ when the flow rate is reduced or is not distilled, increasing the temperature by 3-5 ℃ each time, obtaining an emulsion after 1-3h, and drying under vacuum reduced pressure to obtain desloratadine-cucurbit [7] urea supramolecular compound powder; taking 10g of the powder, crushing and sieving, adding 70g of dextrin (filling agent), 5g of methylcellulose (adhesive), 3g of low-substituted hydroxypropyl cellulose (disintegrant) and 2g of superfine silica gel powder (glidant), sieving, and filling into hollow capsules to obtain the capsule.
Comparative example 1 Desloratadine supramolecular Compounds
The preparation method comprises the following steps:
the molar ratio of desloratadine to beta-cyclodextrin is 2: 1.
Dissolving desloratadine in 100ml of ethanol, and dissolving the desloratadine by ultrasonic waves to obtain a solution A; dissolving beta-cyclodextrin in 200ml of water, and dissolving by ultrasonic to obtain a solution B; slowly mixing solution A and solution B, heating at 25 deg.C, depressurizing, rotary distilling, observing flow rate of distillate, increasing water bath temperature to 40 deg.C gradually when flow rate is reduced or no longer distilled, increasing temperature by 3-5 deg.C each time, obtaining emulsion after 1-3 hr, and vacuum drying under reduced pressure.
Comparative example 2 Desloratadine supramolecular Compounds
The preparation method comprises the following steps:
the mol ratio of desloratadine to cucurbit [7] uril is 1: 2.
Dissolving desloratadine in 100ml of ethanol, and dissolving the desloratadine by ultrasonic waves to obtain a solution A; dissolving cucurbituril in 200ml of water, and performing ultrasonic dissolution to obtain a solution B; slowly mixing solution A and solution B, heating at 25 deg.C, depressurizing, rotary distilling, observing flow rate of distillate, increasing water bath temperature to 40 deg.C gradually when flow rate is reduced or no longer distilled, increasing temperature by 3-5 deg.C each time, obtaining emulsion after 1-3 hr, and vacuum drying under reduced pressure.
Comparative example 3 Desloratadine supramolecular Compounds
The preparation method comprises the following steps:
dissolving desloratadine in 100ml of ethanol, and dissolving the desloratadine by ultrasonic waves to obtain a solution A; dissolving cucurbituril in 200ml of ethanol, and performing ultrasonic dissolution to obtain a solution B; slowly mixing solution A and solution B, heating at 25 deg.C, depressurizing, rotary distilling, observing flow rate of distillate, increasing water bath temperature to 40 deg.C gradually when flow rate is reduced or no longer distilled, increasing temperature by 3-5 deg.C each time, obtaining emulsion after 1-3 hr, and vacuum drying under reduced pressure.
Comparative example 4: desloratadine tablet (en x)
Verification examples
First, quality evaluation
1. Yield of
Table 1 examples and comparative examples desloratadine supramolecular compound synthesis yields
As can be seen from the yields in Table 1, in examples 1-4, in the case of screening the carrier material, the yield was highest, reaching 95.64%, in example 2, in which cucurbit [7] urea was used as the main molecule; examples 5-9 screening experiments on the molar ratio of desloratadine to cucurbit [7] urea revealed that the yields of examples 5, 6, 7 were higher when desloratadine and cucurbit [7] urea were added in a molar ratio of 1-3: 1; in addition, the addition amount and solvent of desloratadine and cucurbit [7] uril have a large influence on the yield. The yield of the comparative example is low.
2. Drug loading
Table 2 drug loading of desloratadine supramolecular compounds of examples and comparative examples
As can be seen from the drug loading rates in Table 2, the molar ratio of the carrier material, desloratadine and the carrier material, the addition amounts of desloratadine and cucurbit [7] urea, and the drug loading rate of the solvent also have a great influence. The drug loading of the comparative examples was lower than that of the examples of the present invention.
3. Content of related substance
TABLE 3 examples and comparative examples concerning the content of substances
As can be seen from the content of related substances in Table 2, the preparation of desloratadine supramolecules or desloratadine prepared by the embodiment of the invention has high stability, and the content of related substances is obviously lower than that of the comparative examples and the commercial preparations.
Second, pharmacological experiment
The inventors conducted relevant pharmacodynamic experimental studies to demonstrate the efficacy of desloratadine formulations of the present invention in treating allergic rhinitis. It should be noted that the drugs selected by the pharmacodynamic tests described below are the drugs obtained by the representative formulation, dosage form and preparation method of the present invention; the inventor also carries out pharmacodynamic experiments on the medicines obtained by other formulas, dosage forms and preparation methods, and the experimental results show that the medicines obtained by other formulas, dosage forms and preparation methods have the same or similar effects, but the medicines are not listed in the invention due to space limitation.
The inventor explains that the following experimental studies are carried out on the basis of the safety of the drug proved by acute toxicity tests and long-term toxicity tests, and the administration dose in the experimental studies is within a safe dose range.
1 Material
1.1 Experimental drugs and reagents
1.1.1 medicaments
The invention can be prepared into tablets obtained in example 17, granules obtained in example 18 and capsules obtained in example 19;
comparative example 4: desloratadine tablet (en x)
Ovalbumin (OVA);
aluminum hydroxide gel.
1.1.2 dosage
Example 17: 0.225mg/kg (low dose), 0.45mg/kg (medium dose), 0.9mg/kg (high dose);
example 18: 0.45 mg/kg;
example 19: 0.45 mg/kg;
comparative example 4: 0.45 mg/kg.
1.2 Experimental animals:
SD rat, SPF grade, 180-: SYXK (lu) 20180008, supplied by lumnan pharmaceutical group ltd, was acclimatized for 1 week under standard conditions prior to the experiment.
2. Method of producing a composite material
2.1 Molding method
Molding: an Ovalbumin (OVA) sensitization model is established by taking 90 rats (male and female halves): basal sensitization is carried out by intraperitoneal injection of 0.5ml of sterile normal saline containing 10 mu g of OVA and 1mg of aluminum hydroxide gel on the 1 st day, intensified sensitization is carried out by intraperitoneal injection of 0.5ml of sterile normal saline containing l0 mu g of OVA on the 5 th day, 1 time per day, 50 mu l of 2mg/ml OVA is dripped into the nose on the 6 th day, the rats are stimulated for 14 consecutive days, and sneezing, nose scratching and nasal discharge are observed, and finally 87 rats are successfully modeled (41 female rats and 46 male rats).
Blank: 10 rats (male and female halves) were collected and sham-sensitized and sham-stimulated with sterile physiological saline in the same manner as described above.
2.2 groups of Experimental animals
The SD rats successfully molded were randomly divided into model groups, comparative example 4 group, three dose groups of example 17 (high, medium, low), example 18 group, and example 19 group, each of which was 10 animals each with male and female halves.
Blank group: 10 SD rats, male and female halves.
2.3 administration of drugs
The rats in each administration group were gavaged with 1.12 corresponding drugs, and the rats in the blank group and the model group were gavaged with an equal amount of physiological saline for 1 time per day for 7 days.
3 observation index
3.1 rat status score
The nasal discharge, sneezing frequency and nasal itching degree were recorded by scoring. The sneezing, nasal discharge and nasal discharge actions of the rats are observed, each index is subjected to superposition quantitative scoring, and the total score exceeds 5, so that the model building is successful. The scoring method is shown in Table 4.
TABLE 4 allergic rhinitis Condition score criteria
3.2 detection of IL-2, IL-4 in serum samples
Taking 0.1-0.2ml of venous blood from rat tail with 1ml disposable syringe, placing the venous blood into 1ml centrifuge tube, and standing at room temperature for 30 min. Centrifuging the blood at 4 deg.C for 10min (3000r/min), separating serum into 1ml centrifuge tubes, and measuring IL-2 and IL-4 content in the serum sample by ELIS method. The color is developed with the substrate TMB, which is converted to blue by the catalysis of peroxidase and to the final yellow color by the action of an acid. The shade of the color is positively correlated with IL-2 and IL-4 in the sample. The absorbance was measured at a wavelength of 450nm with a microplate reader, and the sample concentration was calculated.
3.3 detection of cellular immune factors
Taking 0.1-0.2ml of venous blood from rat tail with 1ml disposable syringe, placing the venous blood into 1ml centrifuge tube, and standing at room temperature for 30 min. Centrifuging blood at 4 deg.C for 10min (3000r/min), separating serum into 1ml centrifuge tubes, and detecting total immunoglobulin E (T-IgE) and Eosinophil Cationic Protein (ECP) content in serum respectively.
4. Statistical treatment
Statistical analysis is carried out on the obtained data by adopting SPSS22.0 software, and the data is measured
The results are shown in the following table, wherein the comparison among the groups is carried out by adopting one-factor analysis of variance, and the analysis between the two groups is carried out by adopting an independent sample T test mode. With P<A difference of 0.05 is statistically significant.
5. Results and conclusions
5.1 behavioral State in rats
The results of comparing the allergic reaction behavior scores of the rats with rhinocnesmus, nasal mucus and sneeze (see table 5) show that when the rats are dosed for 0 day, the model group, the three dose groups of example 17 (high, medium and low), the example 18 group and the example 19 group are compared with the blank group, the difference has statistical significance (P is less than 0.01), and the model building is successful.
TABLE 5 scoring of allergic rhinitis symptoms in rats
Note: p < 0.01 compared to blank;
in contrast to the model set,％P＜0.01；
in comparison with the comparative example 4, the present inventors have conducted a study,#P＜0.01。
when the rats were administered 7d, the behavior of the rats was observed and the scores were given, and it was found in table 5 that the model group had self-healing in some cases after the rats were administered 7 days, and that P < 0.01 in the example 17 (high, medium and low dose groups), the example 18 group, the example 19 group and the comparative example 4 group was superior to the model group in the treatment effect on rat rhinitis, i.e., the treatment effects on sneezing and rhinorrhea of rat allergic rhinitis were significantly improved, and P < 0.01 in the example 17 (high, medium and low dose groups), the example 18 group and the example 19 group and the comparative example 4 group were superior to the treatment effect on the example 17 (high, medium and low dose groups), the example 18 group and the example 19 group and the comparative example 4 group.
5.2 expression of IL-2 and IL-4 levels in serum samples
TABLE 6 rat serum IL-2 content expression
Note: p < 0.01 compared to blank;
in contrast to the model set,％P＜0.01；
in comparison with the comparative example 4, the present inventors have conducted a study,#P＜0.01。
as is clear from Table 6, the group of example 17 (high, medium and low dose group), the group of example 18, the group of example 19 and the group of comparative example 4 were compared with the model group％P is less than 0.01, which shows that the expression of the IL-2 content in the serum of the rat can be reduced, and compared with the group of the comparative example 4, the effects of the examples 17 to 19 of the invention on reducing the IL-2 content in the serum of the rat are more obvious.
TABLE 7 rat serum IL-4 content expression
Note: p < 0.01 compared to blank;
in contrast to the model set,％P＜0.01；
comparative example 4 phaseThe ratio of the amount of the acid to the amount of the water,#P＜0.01，@P＜0.05。
as can be seen from Table 7, examples 17 to 19 of the present invention showed more significant effects of reducing IL-4 level in rat serum than the group of comparative example 4.
5.3 levels of Ig E, ECP levels in rat serum samples
TABLE 8 expression of serum Ig E, ECP content in rats
Note: p < 0.01 compared to blank;
in contrast to the model set,％P＜0.01；
in comparison with the comparative example 4, the present inventors have conducted a study,#P＜0.01。
as can be seen from Table 8, P < 0.01 was found in the model group, example 17 (high, medium, and low dose group), example 18, example 19, and comparative example 4, compared with the blank group; the P of the example 17 (high, medium and low dose groups), the example 18 group, the example 19 group and the comparative example 4 group is less than 0.01 compared with the model group; example 17 (high, medium, low dose group), example 18 group, example 19 group and comparative example 4 group, P < 0.01.
In conclusion, the therapeutic effects of example 17 (high, medium and low dose groups), example 18 and example 19 groups of the present invention on rat allergic rhinitis are better than those of the commercially available desloratadine tablets of comparative example 4, and the effect of the low dose group of the tablet of example 17 is also better than that of comparative example 4, which shows that the present invention combines desloratadine and macrocyclic compound into a supramolecular compound as an intermediate for preparing a preparation, and the therapeutic effect of desloratadine on allergic rhinitis can be improved.
Claims (10)
1. A desloratadine preparation is characterized by comprising desloratadine, a carrier material and a pharmaceutically acceptable auxiliary material, wherein the desloratadine and the carrier material are combined through intermolecular force to form a supramolecular compound.
2. A desloratadine formulation according to claim 1 wherein the dosage of loratadine and carrier material is in a range of 1-5: 1.
3. a desloratadine formulation according to claim 1 wherein the carrier material is a macrocyclic compound having cavities or channels.
4. A desloratadine formulation according to claim 2, wherein the macrocyclic compound is cucurbituril, including cucurbit [5] urea, cucurbit [6] urea, cucurbit [7] urea, cucurbit [8] urea, cucurbit [10] urea, cucurbit [14] urea, preferably cucurbit [7] urea.
5. A desloratadine formulation according to claim 1 wherein the desloratadine is used as a pharmaceutical guest molecule and the carrier material is used as a host molecule, both of which form supramolecular compounds through hydrogen bonding, pi-pi stacking, electrostatic interactions and hydrophobic interactions.
6. A desloratadine formulation according to claim 1 wherein the loratadine and carrier material are combined in a molar ratio of 1:1 or/and 2: 1.
7. A desloratadine formulation according to claim 1 wherein the supramolecular compound further comprises water molecules and/or solvent molecules.
8. The desloratadine formulation according to claim 1 wherein the supramolecular compound can be formulated with pharmaceutically acceptable excipients including but not limited to tablets, capsules, granules, pills, suspensions, ointments, emulsions, aerosols.
9. A process for preparing a desloratadine formulation of claim 1 comprising the steps of:
(1) preparation of desloratadine supramolecular compounds: dissolving desloratadine and a carrier material in a solvent respectively,
mixing, rotary steaming under reduced pressure for 1-3 hr to obtain emulsion, and vacuum drying;
(2) adding pharmaceutically acceptable auxiliary materials into the desloratadine supramolecular compound obtained in the step (1), and preparing the preparation according to a conventional method.
10. The method of claim 9, wherein the step (1) is: dissolving desloratadine in one of methanol, ethanol, propylene glycol and water, and dissolving the desloratadine in the solvent by ultrasonic waves to obtain a solution A; dissolving a carrier material in water, and dissolving the carrier material by ultrasonic to obtain a solution B; slowly mixing the solution A and the solution B, heating in a water bath kettle, reducing pressure, steaming, gradually increasing the heating temperature from 25 deg.C to 40 deg.C for 1-3 hr to obtain emulsion, and vacuum drying under reduced pressure.
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