CN117899164A - Novel aerosolized dosage form system and its use in the preparation of a medicament - Google Patents
Novel aerosolized dosage form system and its use in the preparation of a medicament Download PDFInfo
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Abstract
The invention provides a novel atomizing dosage form system and application thereof in preparation of medicines, and relates to the technical field of atomizing inhalation, wherein the novel atomizing dosage form system comprises the following components: lily extract, platycodon root extract, tangerine pith extract, ginkgo extract, bergapten, arundoin, imperatorin, fritillaria cirrhosa extract, dexpanthenol, silymarin, osmotic pressure regulator and water. In addition, the system also comprises an inhalation aerosolization device, and the novel aerosolized dosage form system of the invention is more acceptable to long-term smokers and can be used for the targeted treatment of chronic diseases.
Description
Technical Field
The invention relates to the technical field of aerosol inhalation, in particular to a novel aerosol formulation system and application thereof in preparation of medicines.
Background
The long-term smoking can cause various chronic diseases, such as pulmonary nodules, chronic cardiovascular and cerebrovascular diseases, neurodegenerative diseases, cancers and the like, and the current control strategies mainly comprise reducing the ingestion of harmful substances such as nicotine and the like by means of electronic cigarettes, advanced smoking equipment, auxiliary smoking equipment and the like, and controlling patients suffering from related diseases mainly in various administration forms. However, even if there are various modes and methods for treating and preventing medicines, the existing administration mode has strong limitations on occurrence and development of diseases, such as the limitation that a smoker cannot change his or her living habit and the treatment means of various chronic patients, and the non-uniform dispersion of medicines in the lung. In addition, there are differences in the rate of absorption, dose control and patient compliance for inhaled aerosolized medicaments.
Related prior art, such as patent CN1561213a, discloses pharmaceutical compositions comprising nicotine, which comprise chocolate, methods of preparing the compositions, and the use of the compositions in various treatments, such as nicotine replacement therapy. The invention discloses the above composition and a device for transdermal administration of nicotine for the treatment of cigarette dependency, cigarette interruption, reduction and temporary withdrawal, and for the treatment of Alzheimer's disease, parkinson's disease, ulcerative colitis and/or Tourette's syndrome. The related art of the above patent is mainly focused on the field of nicotine delivery, nicotine replacement therapy or herbal cigarettes. These patents are generally directed to the management of nicotine addiction, rather than to the integrated treatment and prevention of a variety of chronic diseases.
In addition, patent CN115068450a discloses a fodosteine aerosol inhalation solution composition, a pharmaceutical assembly and its application, the assembly comprising: (1) An aerosol inhalation solution composition comprising the active ingredient Fudosteine or a pharmaceutically acceptable salt thereof, a pH regulator, water for injection; the pH of the composition is 3.7-3.9; (2) an atomizing device for use with said composition; the Fudosteine aerosol inhalation solution composition and the components thereof have the advantages of small effective dose, high effective speed, high drug delivery efficiency and the like, and particularly have remarkable effects on the aspect of treatment of tracheal and main tracheal diseases. Also as disclosed in patent CN114931565A, a method for preparing a spray inhalation solution of quassia is disclosed, wherein the components of the spray inhalation solution of quassia comprise quassia extract, osmotic pressure regulator, surfactant, pH regulator and water for injection. The medicine is directly inhaled into the respiratory system in an atomization mode through the atomizer, acts on focuses such as bronchus and lung, is quick in absorption and quick in action, improves the concentration of medicine in the respiratory tract, reduces the administration dosage, reduces the distribution of the medicine in other tissues, reduces the side effect of the medicine, and realizes low-dosage and quick and effective treatment.
However, the above technology has the problems of complex system device or unacceptable for long-term smoking patients, and aiming at the problems existing in the prior art, it is necessary to find a novel atomized dosage form system and application thereof in preparation of medicines.
Disclosure of Invention
Aiming at the problems existing in the prior art, the invention provides a novel atomization dosage form system and application thereof in preparation of medicines, and the novel atomization dosage form system is more acceptable for long-term smoking patients and can be used for directional treatment of chronic diseases.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
The invention provides an atomized dosage form system, which comprises the following medicaments: lily extract, platycodon root extract, tangerine pith extract, ginkgo extract, bergapten, arundoin, imperatorin, fritillaria cirrhosa extract, dexpanthenol, silymarin, osmotic pressure regulator and water.
Further, the atomized dosage form system comprises the following medicines in parts by weight: 0.1-0.5 part of lily extract, 0.1-0.6 part of platycodon grandiflorum extract, 0.2-0.5 part of orange pith extract, 0.05-0.1 part of ginkgo biloba extract, 0.01-0.09 part of bergapten, 0.01-0.06 part of arundoin, 0.02-0.1 part of imperatorin, 0.2-0.8 part of fritillaria cirrhosa extract, 0.001-0.01 part of dexpanthenol, 0.02-0.08 part of silymarin, 0.05-0.2 part of osmotic pressure regulator and 75-95 parts of water.
In some preferred embodiments, the amount of lily extract in the medicament of the aerosolized dosage form system of the present invention is in the range of from 0.1-0.5 parts by weight, preferably 0.1, 0.2, 0.3, 0.4, 0.5 or any value in between the foregoing values.
In some preferred embodiments, the amount of platycodon grandiflorum extract in the medicament of the aerosolized dosage form system of the present invention is in the range of 0.1-0.6 parts by weight, preferably 0.1, 0.2, 0.3, 0.4, 0.5, 0.6 or any value therebetween.
In some preferred embodiments, the amount of orange extract in the medicament of the aerosolized dosage form system of the present invention is in the range of from 0.2-0.5 parts by weight, preferably 0.2, 0.3, 0.4, 0.5 or any value in between the foregoing values.
In some preferred embodiments, the amount of ginkgo extract in the medicament of the aerosolized dosage form system of the present invention is from 0.05-0.1 parts by weight, preferably 0.05, 0.06, 0.07, 0.08, 0.09, 0.1 or any number therebetween.
In some preferred embodiments, the bergapten extract is used in the medicament of the aerosolized dosage form system of the present invention in an amount of from 0.01-0.09 parts by weight, preferably 0.01, 0.05, 0.06, 0.07, 0.08, 0.09 or any number therebetween.
In some preferred embodiments, the amount of arundoin extract used in the pharmaceutical of the aerosolized dosage form system of the present invention is from 0.01-0.06 parts by weight, preferably 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, or any number in between the foregoing values.
In some preferred embodiments, the imperatorin extract is used in the medicament of the aerosolized dosage form system of the present invention in an amount of from 0.02 to 0.1 parts by weight, preferably 0.02, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1 or any number in between the foregoing values.
In some preferred embodiments, the fritillaria cirrhosa extract is used in the pharmaceutical of the present aerosolized dosage form system in an amount of 0.2-0.8 parts by weight, preferably 0.2, 0.3, 0.4, 0.5, 0.8 or any value in between the foregoing values.
In some preferred embodiments, the fritillaria cirrhosa extract is used in the pharmaceutical of the present aerosolized dosage form system in an amount of 0.2-0.8 parts by weight, preferably 0.2, 0.3, 0.4, 0.5, 0.8 or any value in between the foregoing values.
In some preferred embodiments, the amount of dexpanthenol in the medicament of the aerosolized dosage form system of the present invention is from 0.001-0.01 parts by weight, preferably 0.001, 0.005, 0.008, 0.01 or any number in between the foregoing.
In some preferred embodiments, the amount of silymarin in the medicament of the aerosolized dosage form system of the present invention is in the range of from 0.02 to 0.08 parts by weight, preferably 0.02, 0.03, 0.04, 0.05, 0.08 or any value therebetween.
In some preferred embodiments, the osmolality adjusting agent is used in the medicament of the aerosolized dosage form system of the present invention in an amount of 0.05-0.2 parts by weight, preferably 0.05, 0.08, 0.1, 0.15, 0.2 or any value in between.
In some preferred embodiments, the amount of water used in the medicament of the aerosolized dosage form system of the present invention is from 75-95 parts by weight, preferably 75, 80, 85, 90, 95 or any value in between the foregoing.
Preferably, the atomized dosage form system comprises the following medicines in parts by weight: 0.4 part of lily extract, 0.5 part of platycodon grandiflorum extract, 0.3 part of tangerine pith extract, 0.06 part of ginkgo extract, 0.05 part of bergapten, 0.05 part of arundoin, 0.05 part of imperatorin, 0.3 part of fritillaria cirrhosa extract, 0.008 part of dexpanthenol, 0.05 part of silymarin, 0.1 part of osmotic pressure regulator and 90 parts of water.
Preferably, the weight ratio of the tangerine pith extract, bergapten and fritillaria cirrhosa extract is (0.2-0.5): (0.01-0.09): (0.2-0.8). Further preferably 0.3:0.05:0.3.
Further, the osmolality adjusting agent includes one or more of sodium chloride, glucose, and glycerin.
Further, the aerosolized dosage form system also includes an inhalation aerosolization device.
Further, the inhalation atomization device consists of an elongated coiled object and a cigarette holder.
Further, the method of preparing the aerosolized dosage form system comprises the steps of:
(1) Mixing Bulbus Lilii extract, radix Platycodi extract, fructus Citri Tangerinae extract, semen Ginkgo extract, bergapten, arundoin, imperatorin, bulbus Fritillariae Cirrhosae extract, dexpanthenol, silymarin, and osmotic pressure regulator, and dissolving in water;
(2) Adjusting the pH to obtain an inhalation composition solution;
(3) Filtering the inhalation composition solution, and adding into an inhalation atomization device.
Furthermore, the atomized dosage form system provided by the invention can be applied to preparing a medicine product for treating chronic diseases.
Further, the site of administration of the drug includes one or more of the nose, throat, trachea, esophagus, and main bronchi.
Further, the chronic diseases include pulmonary nodules, chronic cardiovascular and cerebrovascular diseases, neurodegenerative diseases or cancers.
Further, the pH is 3-8.5; preferably 6.
The invention has the technical effects that:
1. The novel aerosolized dosage form system of the present invention is user friendly: because the appearance is similar to cigarettes, the novel administration mode is more acceptable for long-term smokers, and the difficulty of changing smoking habits is reduced;
2. The novel aerosolized dosage form system of the present invention can be used for targeted therapy: aiming at different chronic diseases, such as pulmonary nodules, chronic cardiovascular and cerebrovascular diseases, neurodegenerative diseases or cancers, the directional treatment can be realized by adjusting the selection and compatibility of the medicines, so that the treatment accuracy is improved;
3. the novel atomized dosage form system has the advantages of convenience: the novel administration mode is more convenient and fast to use, and a user can use the novel administration mode anytime and anywhere without being limited by time and places;
4. The novel atomized formulation system of the invention has wide applicability: the novel administration mode has wide applicability because of being applicable to treatment and prevention of various chronic diseases.
5. The invention avoids the problems that the atomized liquid has strong irritation and is easy to choke when the osmotic pressure regulator is not added, and the stability of the product is affected after the osmotic pressure regulator is added through the synergistic effect between the components.
Detailed Description
Other advantages and effects of the present invention will become apparent to those skilled in the art from the following disclosure, which describes the embodiments of the present invention with reference to specific examples. The invention may be practiced or carried out in other embodiments that depart from the specific details, and the details of the present description may be modified or varied from the spirit and scope of the present invention.
Before the embodiments of the invention are explained in further detail, it is to be understood that the invention is not limited in its scope to the particular embodiments described below; it is also to be understood that the terminology used in the examples of the invention is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the invention.
Where numerical ranges are provided in the examples, it is understood that unless otherwise stated herein, both endpoints of each numerical range and any number between the two endpoints are significant both in the numerical range. 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 to which this invention belongs.
It is worth noting that the lily extract (MF-000448), the platycodon grandiflorum extract (MF-007295), the tangerine pith extract (MF-000582) and the ginkgo biloba extract (MF-005139) used in the invention are purchased from Miwa biological science and technology limited company of Xinyang, bergapten CAS number is 484-20-8, arundoin CAS number is 4555-56-0, imperatorin CAS number is 17904-55-1, silymarin CAS number is 65666-07-1, and the other raw materials are all common commercial products, so the sources are not particularly limited.
TABLE 1 pharmaceutical compositions (unit: parts by weight) in the misting formulation system of the invention
The method of making the novel aerosolized dosage form system of examples 1-3 includes the steps of:
(1) Mixing Bulbus Lilii extract, radix Platycodi extract, fructus Citri Tangerinae extract, semen Ginkgo extract, bergapten, arundoin, imperatorin, bulbus Fritillariae Cirrhosae extract, dexpanthenol, silymarin, and osmotic pressure regulator, and dissolving in water;
(2) Adjusting the pH to 6 to obtain an inhalation composition solution;
(3) Filtering the inhalation composition solution, and adding into an inhalation atomization device.
The inhalation atomizing device takes on the shape of cigarettes and is specifically composed of an elongated coiled object and a cigarette holder.
The misting dosage form systems of comparative examples 1-3 were prepared in the same manner as in examples 1-3 except that no portion of the ingredients were added to the inhalation composition.
Comparative example 4
The only difference from example 3 is that no orange extract, fritillaria cirrhosa extract and silymarin were added.
The preparation method comprises the following steps:
(1) Mixing 0.4 part by weight of lily extract, 0.5 part by weight of platycodon grandiflorum extract, 0.06 part by weight of ginkgo biloba extract, 0.05 part by weight of bergapten, 0.050 part by weight of arundoin, 0.05 part by weight of imperatorin, 0.008 part by weight of dexpanthenol and 0.1 part by weight of osmotic pressure regulator, and adding into 90 parts by weight of water for dissolution;
(2) Adjusting the pH to 6 to obtain an inhalation composition solution;
(3) Filtering the inhalation composition solution, and adding into an inhalation atomization device.
The inhalation atomizing device takes on the shape of cigarettes and is specifically composed of an elongated coiled object and a cigarette holder.
The lung nodule refers to focal circular compact shadows with various sizes, clear edges or blurred edges and diameters less than or equal to 3cm on lung images, and partial researches show that a great amount of Th 1-like cell factors such as IL-2, TNF-alpha and the like are expressed in alveolar lavage fluid of a patient suffering from the lung nodule disease, which indicates that the interaction of T lymphocytes and macrophages causes the journey of granuloma. Cytokine expression plays an important role in the development and repair of lung disease, for example IL-10 and IFN-gamma play a role in the repair of lung tissue as traditional Chinese medicine. Therefore, TGF-beta 1, TNF-alpha, IFN-gamma and IL-10 are selected to examine the action of the novel atomization formulation system on cytokines, and a granulomatous nodular animal test is carried out to further examine the apparent condition of lung nodules.
Test 1:
1.1 test animals:
SD rats, SPF grade, male, 9 week old, body weight 200+ -20 g, were randomly divided into blank control group, model control group, examples 1-3 group and comparative examples 1-4 group, each group of 10 rats.
1.2 Test method:
After 1 week of adaptive feeding, rats were anesthetized with sodium pentobarbital, and the model control group and rats of each of the examples and comparative examples were injected with bleomycin solution at a dose of 5mg/kg, and the blank control group was given an equivalent amount of physiological saline. On day 3 after the end of molding, each of the drugs of each of the present invention was administered by aerosol inhalation of the examples and comparative examples at an amount of 1.5mL/kg, the model control was given an equivalent amount of physiological saline by aerosol inhalation at an administration frequency of 1 time/day for a total of 28 days, rats were sacrificed after the end of molding, lung tissue was removed, right lung lobes were added to physiological saline at a mass-to-volume ratio of 1g:9mL, homogenized, centrifuged at4℃for 20 minutes, and the supernatant was used to measure the contents of TGF- β1, TNF- α, IFN- γ and IL-10 in the lung tissue, and the results were counted in tables 2 to 5.
1.3 Test results:
TABLE 2 test results of the rat lung tissue cytokine TGF-beta 1 in the present invention
TABLE 3 test results of the rat lung tissue cytokine TNF-alpha in the present invention
TABLE 4 test results of the rat lung tissue cytokine IFN-gamma in the present invention
TABLE 5 test results of the rat lung tissue cytokine IL-10 in the invention
Test 2:
2.1 Test animals:
c57BL/6 mice, SPF grade, female, 6-8 weeks old, weighing 20+ -2 g, were randomly divided into a blank group, example 1-3 groups and comparative example 1-4 groups, each group of 10 mice.
2.2 The test method comprises the following steps:
After 1 week of adaptive feeding, the mice were pre-sensitized by intraperitoneal injection with 0.25mL of inactivated Propionibacterium acnes at a concentration of 2mg/mL, and by intratracheal choking with inactivated Propionibacterium acnes at a concentration of 10mg/mL at days 7, 14, and 21. At the same time, from day 7, each of the drugs of the present invention was administered by aerosol inhalation in each of the examples and the comparative examples at an amount of 1.5mL/kg, and the blank group was administered by aerosol inhalation with an equivalent amount of physiological saline at a frequency of 2 times/day for a total of 14 days. Mice were anesthetized with sodium pentobarbital 1h after the last administration and dissected, and the number and size of pulmonary granulomas in the mice were counted (average value was calculated), and the results were counted to table 6.
2.3 Test results:
TABLE 6 number and size of the sarcomas and nodules of mice of each group in the invention
Note that:
In tables 2-6 of the present invention, superscript # indicates that the model control group has a significant difference in p <0.05 compared to the blank control group;
superscript x indicates that p < 0.05, i.e. there is a significant difference compared to the model control group;
The superscript letters a, b, c, d indicate that p < 0.05, i.e., there is a significant difference, compared to comparative example 1, comparative example 2, comparative example 3, comparative example 4, respectively.
According to the test results of the invention, TGF-beta 1, TNF-alpha, IFN-gamma and IL-10 in the lung tissues of rats in the model control group are improved, and compared with the blank control group, the improvement of IFN-gamma and IL-10 in the model control group can be compensatory improvement after lung tissue injury, after the administration of the novel atomization type system in each example group, the TGF-beta 1 and TNF-alpha contents of rats in the invention are reduced compared with the model control group, and the IFN-gamma and IL-10 are improved compared with the model control group, and the improvement of the IFN-gamma and the IL-10 is obviously different (p < 0.05). Furthermore, the groups of examples 1-3 in the present invention all have significant differences (p < 0.05) with respect to the TGF-. Beta.1, TNF-. Alpha., IFN-. Gamma.and IL-10 content in rat lung tissue as compared to the respective comparative groups.
In the granulomatous nodular animal test, the number of granulomatous nodules and the average size of granulomatous nodules in mice of each example group were significantly smaller than that of the blank group, with significant differences (p < 0.05), and in addition, the number and size of granulomatous nodules were significantly different (p < 0.05) between each example group and the comparative group.
The above results, taken together, demonstrate that the novel aerosolized dosage form system of the present invention is effective in treating chronic diseases such as pulmonary nodules.
Finally, it should be noted that the above description is only for illustrating the technical solution of the present invention, and not for limiting the scope of the present invention, and that the simple modification and equivalent substitution of the technical solution of the present invention can be made by those skilled in the art without departing from the spirit and scope of the technical solution of the present invention.
Claims (10)
1. An aerosolized dosage form system, characterized by: comprises the following medicaments: lily extract, platycodon root extract, tangerine pith extract, ginkgo extract, bergapten, arundoin, imperatorin, fritillaria cirrhosa extract, dexpanthenol, silymarin, osmotic pressure regulator and water.
2. The aerosolized dosage form system of claim 1, wherein: the medicine comprises the following components in parts by weight: 0.1-0.5 part of lily extract, 0.1-0.6 part of platycodon grandiflorum extract, 0.2-0.5 part of orange pith extract, 0.05-0.1 part of ginkgo biloba extract, 0.01-0.09 part of bergapten, 0.01-0.06 part of arundoin, 0.02-0.1 part of imperatorin, 0.2-0.8 part of fritillaria cirrhosa extract, 0.001-0.01 part of dexpanthenol, 0.02-0.08 part of silymarin, 0.05-0.2 part of osmotic pressure regulator and 75-95 parts of water.
3. The aerosolized dosage form system of claim 2, wherein: the medicine comprises the following components in parts by weight: 0.4 part of lily extract, 0.5 part of platycodon grandiflorum extract, 0.3 part of tangerine pith extract, 0.06 part of ginkgo extract, 0.05 part of bergapten, 0.05 part of arundoin, 0.05 part of imperatorin, 0.3 part of fritillaria cirrhosa extract, 0.008 part of dexpanthenol, 0.05 part of silymarin, 0.1 part of osmotic pressure regulator and 90 parts of water.
4. The aerosolized dosage form system of claim 1, wherein: the osmolality adjusting agent includes one or more of sodium chloride, glucose and glycerin.
5. The aerosolized dosage form system of claim 1, wherein: also included is an inhalation atomizing device.
6. The aerosolized dosage form system of claim 5, wherein: the inhalation atomization device consists of an elongated coiled object and a cigarette holder.
7. The aerosolized dosage form system of claim 1, wherein: the preparation method of the atomized dosage form system comprises the following steps:
(1) Mixing Bulbus Lilii extract, radix Platycodi extract, fructus Citri Tangerinae extract, semen Ginkgo extract, bergapten, arundoin, imperatorin, bulbus Fritillariae Cirrhosae extract, dexpanthenol, silymarin, and osmotic pressure regulator, and dissolving in water;
(2) Adjusting the pH to obtain an inhalation composition solution;
(3) Filtering the inhalation composition solution, and adding into an inhalation atomization device.
8. Use of an aerosolized dosage form system according to any one of claims 1-7 in the manufacture of a pharmaceutical product for the treatment of chronic diseases.
9. The use according to claim 8, characterized in that: the site of administration of the drug includes one or more of the nose, throat, trachea, esophagus and main bronchi.
10. The use according to claim 8, characterized in that: the chronic diseases comprise pulmonary nodules, chronic cardiovascular and cerebrovascular diseases, neurodegenerative diseases or cancers.
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