CN115531311A - Nanometer suspension containing ibuprofen and preparation method thereof - Google Patents

Nanometer suspension containing ibuprofen and preparation method thereof Download PDF

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CN115531311A
CN115531311A CN202211303144.5A CN202211303144A CN115531311A CN 115531311 A CN115531311 A CN 115531311A CN 202211303144 A CN202211303144 A CN 202211303144A CN 115531311 A CN115531311 A CN 115531311A
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ibuprofen
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宋茁
苏龙
吴岳星
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Shanghai Jialanhai Nanotechnology Group Co ltd
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

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Abstract

The invention discloses a nano suspension containing ibuprofen, which is water-in-oil nano-scale liquid drop, and comprises a water phase component and an oil phase component, wherein the oil phase component comprises medium chain triglyceride and ibuprofen, and the water phase component comprises pure water, glycerol, a frankincense extract and a white willow bark extract. Correspondingly, the invention also discloses a preparation method of the ibuprofen-containing nano suspension. The nano suspension provided by the invention can increase the solubility of water-insoluble ibuprofen, reduce the administration dosage of ibuprofen, improve the absorption rate and reduce the side effects of drugs.

Description

Nanometer suspension containing ibuprofen and preparation method thereof
Technical Field
The invention relates to a medicine and a manufacturing method thereof, in particular to a medicine suspension and a manufacturing method thereof.
Background
Ibuprofen (Ibuprofen) is a non-steroidal anti-inflammatory drug with antipyretic and analgesic effects. Ibuprofen has analgesic and anti-inflammatory effects by inhibiting cyclooxygenase, reducing prostaglandin synthesis, and relieving fever by hypothalamic thermoregulation center.
Ibuprofen is a white crystalline powder, almost insoluble in water. Existing ibuprofen drugs include: ibuprofen oral solution, ibuprofen tablet, ibuprofen capsule, ibuprofen suspension drop, ibuprofen sustained-release capsule, ibuprofen syrup and the like. The ibuprofen suspension drop is mainly used for treating fever caused by common cold or influenza of children and relieving mild to moderate pain of children, such as headache, arthralgia, migraine, toothache, myalgia, neuralgia and dysmenorrheal. Ibuprofen is also used as an external preparation for relieving local pain, such as muscle pain, joint pain, and pain and swelling caused by strain, sprain and sports injuries, and for symptomatic treatment of osteoarthritis.
Oral administration typically requires a relatively large dose, e.g., 200mg to 800mg, due to the water-insolubility of ibuprofen, which may cause ibuprofen to cause some irritation to the digestive system, and adverse gastrointestinal reactions, including dyspepsia, gastric burning, stomach ache, nausea and vomiting, may occur in a small number of long-term users, and gastric ulcers and gastrointestinal bleeding may occur in about 1% of users.
For topical ibuprofen, adverse gastrointestinal effects may also occur due to the higher dose.
Based on this, it is desirable to provide an ibuprofen-containing drug which can increase the solubility of water-insoluble ibuprofen and reduce the dose to reduce the side effects of the drug, provided that the effect is achieved.
Disclosure of Invention
One of the purposes of the invention is to provide a nano suspension containing ibuprofen, which increases the solubility of water-insoluble ibuprofen through nano-processing, thereby reducing the administration dosage of ibuprofen.
In order to achieve the above object, the present invention provides an ibuprofen-containing nanosuspension in the form of water-in-oil nano-sized droplets, comprising an aqueous phase component and an oil phase component, wherein the oil phase component comprises medium chain triglyceride and ibuprofen, and the aqueous phase component comprises pure water, glycerol, boswellia extract and willow bark extract.
The invention increases the solubility of water-insoluble ibuprofen by nano-treatment process, and can reduce the administration dosage of ibuprofen by combining the synergistic effect of the white willow bark extract and the frankincense extract.
The White Willow bark Extract (White Willow Extract) is bark Extract of White Willow (Salix alba L.) belonging to Salicaceae, is rich in Salicin (Salicin), and can be converted into salicylic acid after entering human body, and has anti-inflammatory and pain relieving effects.
Olibanum (frankinesnse), a resin exuded from bark of plant of Boswellia of Burseraceae, has anti-inflammatory, anti-infectious, inflammation relieving and pain relieving effects. The main components of the frankincense include 60-70% of resin, 27-35% of gum and 3-8% of volatile oil. Wherein the main components of the resin are free alpha-Boswellic acid (alpha-Boswellic acid), beta-Boswellic acid (beta-Boswellic acid), conjugated Boswellic acid and Boswellic resinoid (Olibanoresene). Wherein, the small molecular compound acetyl-11-keto-beta-boswellic acid (AKBA) is the most important active component in the frankincense, and the small molecule has the capacity of inhibiting various inflammation-related pathways and the growth of various tumor cells.
The invention increases the specific surface areas of the ibuprofen, the white willow bark extract and the frankincense extract by synergistically adding the ibuprofen, the white willow bark extract and the frankincense extract and assisting the nanocrystallization technology, improves the absorption rates of the ibuprofen, the white willow bark extract and the frankincense extract by utilizing the permeation-promoting effect of glycerol, and avoids the irritation of oral absorption of the ibuprofen, the white willow bark extract and the frankincense extract to gastrointestinal tracts.
The invention can radically change the administration dosage form, can change the traditional oral gastrointestinal absorption way into oral mucosa absorption, ensures that the effective components are absorbed by the oral mucosa and enter the blood circulation to bypass the gastrointestinal tract and directly act on the human body, and avoids the stimulation of the components to the gastrointestinal tract. The oral mucosa administration is an administration way that the medicine is closely contacted with the oral mucosa surface of a human body, absorbed into the circulatory system of the human body through epithelial cells at the position and plays a local or systemic role.
In addition, the nano suspension can also be externally used, and the glycerin and the water in the suspension can hydrate skin cutin, so that the absorption rate of the skin is improved. Moreover, the nano-scale active ingredient particles have stronger capability of penetrating the surface layer of the skin and higher skin absorption rate. Compared with the oral administration of the active ingredients, the oral administration of the traditional Chinese medicine composition has the advantages that the active ingredients are distributed in the whole blood circulation, the active ingredients externally applied to the affected part are enriched in the administration region, and the concentration of the local active ingredients is higher, so that the adverse reaction of the medicine can be finally reduced, and the compliance of a patient is improved.
Further, in some embodiments of the invention, the aqueous phase component further comprises quillaia saponaria bark extract.
Furthermore, the quillaia saponaria bark extract accounts for 0.3-1% of the nano suspension by mass.
As a preferred embodiment, the invention further adds quillaia bark extract as a water-soluble emulsifier. The Quillaja saponaria bark extract is obtained from bark of Quillaja saponaria of Leguminosae, is rich in triterpene saponin, and is ideal pure natural surfactant. The traditional chemical emulsifier is broken through, such as tween-80, span-80 and the like, which can effectively avoid some adverse reactions caused by eating a large amount of traditional chemical emulsifier, and reduce the metabolic burden of human body to the chemical emulsifier.
Further, in some embodiments of the present invention, the water-in-oil nano-sized droplets have a particle size ranging from 50nm to 300nm.
The particle size distribution index (PDI) is low, the particle size is uniform, the molecular weight distribution is uniform, and the stability and the microbial stability are better.
Further, in some embodiments of the present invention, the oil phase component accounts for 60 to 80% by mass of the nanosuspension, and the water phase component accounts for 20 to 40% by mass of the nanosuspension.
Further, in some embodiments of the invention, the ibuprofen comprises 2% to 12% by mass of the nanosuspension.
Further, in some embodiments of the present invention, the white willow bark extract accounts for 0.1% to 1.5% of the nanosuspension by mass.
Further, in some embodiments of the present invention, the boswellia extract accounts for 1-5% by mass of the nanosuspension.
Further, in some embodiments of the invention, the medium chain triglyceride comprises 45% to 70% by weight of the nanosuspension.
Further, in some embodiments of the present invention, the glycerol is present in an amount of 2% to 10% by weight of the nanosuspension.
Further, in some embodiments of the present invention, the aqueous phase component further comprises: at least one of bacteriostatic agent, acidity regulator, sweetener and essence.
Still further, when present, the bacteriostatic agent comprises at least one of: potassium sorbate, sodium benzoate, citric acid, ascorbic acid, sodium citrate; when present, the acidity regulator comprises at least one of: citric acid, sodium citrate, tartaric acid, sodium tartrate, DL-malic acid, lactic acid, DL-sodium malate; when present, the sweetener comprises at least one of: xylitol, stevioside, sucralose, maltitol.
The invention also aims to provide a method for preparing the nano suspension containing the ibuprofen, and the nano suspension containing the ibuprofen can be prepared by the method.
Based on the above object, the present invention also provides a method for preparing ibuprofen-containing nanosuspension, comprising the steps of:
(1) Uniformly mixing and heating all components of the oil phase component, and uniformly mixing and heating all components of the water phase component;
(2) Uniformly mixing the oil phase component and the water phase component together, and carrying out high-speed shearing emulsification treatment to obtain a primary emulsion micron-sized suspension;
(3) And (3) performing nanocrystallization treatment on the colostrum micron-sized suspension by using an ultrahigh-pressure homogenizer, and cooling to obtain the nano-suspension.
Further, in the step (1) of the manufacturing method of the present invention, the oil phase component is heated to 40 to 60 ℃; and/or heating the aqueous phase ingredients to 40-60 ℃.
Further, in the step (2) of the manufacturing method of the present invention, the process parameter of the high-speed shearing emulsification treatment satisfies at least one of the following conditions:
the temperature is 40-60 ℃;
the treatment time is 2min to 8min;
the rotating speed of the high-speed shearing emulsification is 2000rpm to 8000rpm.
Further, in step (3) of the manufacturing process of the present invention, the nanocrystallization step includes: treating with micro-jet ultra-high pressure homogenizer at 100-600bar for at least 1 time; treating with micro-jet ultra-high pressure homogenizer at 200-800bar for at least 1 time.
Compared with the prior art, the nano suspension containing ibuprofen has the advantages and beneficial effects as follows:
the nano suspension containing ibuprofen is a nanoparticle-grade submicron colloidal dispersion, has high drug loading capacity, improves the bioavailability of effective components in a human body, and can reduce the using dose of the effective components, for example, less than 1 ml can be used in each administration.
In the nano suspension containing ibuprofen, the water phase component contains glycerol, which not only can be used as a water phase solvent, but also can be used as a penetration enhancer for mucous membranes and skin, so that the efficiency of ibuprofen, the white willow bark extract and the frankincense extract for penetrating through oral mucous membranes and skin is enhanced. In addition, the invention adopts the glycerol as the emulsifier and is matched with the pure water, so that adverse reactions caused by eating a large amount of the conventional chemical emulsifier can be effectively avoided, and the metabolic burden of a human body on the chemical emulsifier is reduced.
The nano suspension containing ibuprofen increases the specific surface area of the active ingredients through nanocrystallization treatment, and further enhances the absorption rate of the active ingredients by combining the permeation promoting effect of glycerol.
The nano suspension containing ibuprofen can be administrated through oral mucosa, enter blood circulation and play a role of the whole body; can also realize local external administration, such as directly spraying on pain affected parts such as knees, back, elbows and the like, and directly acting on the affected parts after being absorbed by skin, thereby being convenient to use.
The nano suspension containing ibuprofen enables the particle sizes of the ibuprofen, the white willow bark extract and the frankincense extract to reach the nano level through emulsification of the oil phase component and the water phase component, so that the absorption of oral mucosa or skin can be improved, digestion and burden of a liver and kidney system caused by eating a large amount of auxiliary materials in a conventional tablet or capsule, such as capsule skin and filling materials, can be effectively avoided, and further the metabolic burden of a human body can be effectively reduced.
After the nano suspension containing ibuprofen is applied to oral mucosa in a form of spraying by a spraying device, effective components can be absorbed by the oral mucosa or skin and enter systemic circulation to take effect, so that adverse reactions caused by the fact that the effective components enter and stimulate gastrointestinal tracts are avoided. In addition, the nano suspension adopts a spray administration form, so that the swallowing difficulty caused by the overlarge form of the traditional tablet and capsule nutrient supplement products faced by a user is avoided, and the unnecessary psychological fear burden is prevented when the nano suspension is used.
Detailed Description
The ibuprofen-containing nanosuspension and the method for producing the same according to the present invention will be further explained and illustrated with reference to the specific examples, which, however, should not be construed as unduly limiting the technical scope of the invention.
Examples 1 to 6
In the present invention, the ibuprofen-containing nanosuspensions of examples 1 to 6 were prepared using the following steps (1) to (3):
(1) The components of the oil phase ingredients are mixed uniformly and heated, for example, to 40-60 ℃ in some embodiments, according to the composition design of tables 1-1 to 1-6 below; the components of the aqueous phase ingredients are mixed well and heated, for example to 40-60 ℃ in certain embodiments.
(2) Uniformly mixing the oil phase component and the water phase component together, and carrying out high-speed shearing emulsification treatment, wherein: the temperature is controlled to be 40-60 ℃, the processing time is controlled to be 2-8 min, and the rotating speed of high-speed shearing emulsification is controlled to be 2000-8000 rpm.
(3) Performing nanocrystallization treatment on the colostrum micron-sized suspension obtained in the step (2) by using an ultrahigh pressure homogenizer, and treating for at least 1 time, for example 1 time, by using a micro-jet ultrahigh pressure homogenizer under the pressure of 100-600 bar; treating with micro-jet ultra-high pressure homogenizer at 200-800bar for at least 1 time, such as 2 times, and cooling to obtain ibuprofen-containing nanosuspension.
In the present invention, the specific composition design and formulation of the water phase component and the oil phase component of the ibuprofen-containing nanosuspension of examples 1 to 6 are shown in tables 1 to 6 below.
TABLE 1-1 (example 1)
Figure BDA0003904777360000061
Tables 1 to 2 (example 2)
Figure BDA0003904777360000062
Figure BDA0003904777360000071
Tables 1 to 3 (example 3)
Figure BDA0003904777360000072
Tables 1 to 4 (example 4)
Figure BDA0003904777360000073
Tables 1 to 5 (example 5)
Figure BDA0003904777360000081
Tables 1 to 6 (example 6)
Figure BDA0003904777360000082
It should be noted that, although not listed in the above examples 1 to 6, in other examples, citric acid, ascorbic acid, sodium citrate; the acidity regulator may also be used: DL-malic acid, lactic acid, DL-sodium malate; sweeteners may also be used: sucralose and maltitol.
In addition, in each of the above embodiments of the present invention, as a preferred technical Solution, the frankincense extract is 5-Loxin developed and produced by PTL Health Solution company
Figure BDA0003904777360000092
Brand Boswellia serrata extract, which is different from general Boswellia serrata extract containing only 2-3% of AKBA, 5-Loxin
Figure BDA0003904777360000093
The content of AKBA in Olibanum extract is 30%, the concentration of active ingredient is higher, and the extract is applied 13 timesThe results of the pre-bed test and 2 times of human clinical studies prove that the effect is better and stable. Of course, in other embodiments, other boswellia extracts are possible.
In the present invention, based on the compositions designed in the above tables 1-1 to 1-6, the corresponding ibuprofen-containing nanosuspensions can be prepared by the manufacturing method of the above steps (1) to (3), and the following table 2 lists the specific process parameters of the nanosuspensions of examples 1-6 in the above process steps.
Table 2.
Figure BDA0003904777360000091
As can be seen from Table 2 above, the nanosuspensions of examples 1-6 designed by the present invention all meet the design requirements of the present invention in the manufacturing process used in the actual manufacturing.
It can be seen that the ibuprofen-containing nanosuspensions of examples 1-6 can be prepared by the component design and method described in the present invention. The ibuprofen-containing nanosuspensions of examples 1-6 were all water-in-oil nanoscale droplets.
Accelerated stability studies were performed on the ibuprofen-containing nanosuspensions of examples 1 to 6, which were specifically selected to be placed under accelerated conditions (controlled temperature at 40 ℃. + -. 5 ℃ C., controlled relative humidity 75% RH. + -. 10% RH) for 1, 2 and 3 months, respectively, and the contents of active ingredients and the stability of particle size were measured and examined, and the corresponding assay methods are shown in Table 3 below.
Table 3.
Figure BDA0003904777360000101
In addition, the microbial content of the ibuprofen-containing nanosuspensions of examples 1 to 6 was measured, and the measurement items and measurement methods thereof are shown in table 4 below.
Table 4.
Figure BDA0003904777360000102
The results of the above tests are shown in tables 5-1 to 5-6.
TABLE 5-1 (example 1)
Figure BDA0003904777360000103
TABLE 5-2 (example 2)
Figure BDA0003904777360000104
Figure BDA0003904777360000111
Tables 5 to 3 (example 3)
Figure BDA0003904777360000112
Tables 5 to 4 (example 4)
Figure BDA0003904777360000113
Tables 5 to 5 (example 5)
Figure BDA0003904777360000114
Tables 5 to 6 (example 6)
Figure BDA0003904777360000121
As can be seen from the above tables 5-1 to 5-6, the ibuprofen-containing nanosuspensions of examples 1-6 prepared in accordance with the present invention exhibited very excellent stability and microbial stability after being left for 1, 2 and 3 months, respectively, under accelerated conditions (controlled temperature at 40 ℃. + -. 5 ℃, relative humidity 75% RH. + -. 10% RH) in this order.
After being respectively placed for 1, 2 and 3 months in sequence under the accelerated condition, the active ingredient content, the particle size and the microorganism content of the nanosuspensions of the embodiments 1 to 6 all meet the requirements of the scheme, and the nanosuspensions have very good application prospects.
It should be noted that the combination of the features in the present application is not limited to the combination described in the claims of the present application or the combination described in the specific examples, and all the features described in the present application may be freely combined or combined in any manner unless contradicted by each other.
It should also be noted that the above-mentioned embodiments are only specific embodiments of the present invention. It is apparent that the present invention is not limited to the above embodiments and similar changes or modifications can be easily made by those skilled in the art from the disclosure of the present invention and shall fall within the scope of the present invention.

Claims (16)

1. An ibuprofen-containing nanosuspension, wherein the ibuprofen-containing nanosuspension is in the form of water-in-oil nanoscale droplets, the ibuprofen-containing nanosuspension comprises an aqueous phase component and an oil phase component, wherein the oil phase component comprises a medium chain triglyceride and ibuprofen, and the aqueous phase component comprises pure water, glycerol, a frankincense extract and a white willow bark extract.
2. The ibuprofen-containing nanosuspension according to claim 1, wherein the aqueous phase component further comprises quillaja bark extract.
3. The ibuprofen-containing nanosuspension according to claim 2, wherein the quillaja bark extract is present in an amount of 0.3% to 1% by weight of the nanosuspension.
4. The ibuprofen-containing nanosuspension according to claim 1, wherein the water-in-oil nanoscale droplets have a particle size in the range of 50nm to 300nm.
5. The ibuprofen-containing nanosuspension according to claim 1, wherein the oil phase component accounts for 60-80% by mass of the nanosuspension, and the water phase component accounts for 20-40% by mass of the nanosuspension.
6. The ibuprofen-containing nanosuspension according to claim 1, wherein the ibuprofen comprises 2% to 12% by mass of the nanosuspension.
7. The ibuprofen-containing nanosuspension according to claim 1, wherein the white willow bark extract accounts for 0.1-1.5% by mass of the nanosuspension.
8. The ibuprofen-containing nanosuspension according to claim 1, wherein the boswellia extract is present in an amount of 1% to 5% by weight of the nanosuspension.
9. The ibuprofen-containing nanosuspension according to claim 1, wherein the medium chain triglyceride comprises 45% to 70% by mass of the nanosuspension.
10. The ibuprofen-containing nanosuspension according to claim 1, wherein the glycerol comprises 2% to 10% by mass of the nanosuspension.
11. The ibuprofen-containing nanosuspension of claim 1, wherein the aqueous phase component further comprises: at least one of bacteriostatic agent, acidity regulator, sweetener and essence.
12. The ibuprofen-containing nanosuspension of claim 11, wherein when present, the bacteriostatic agent comprises at least one of: potassium sorbate, sodium benzoate, citric acid, ascorbic acid, sodium citrate; when present, the acidity regulator comprises at least one of: citric acid, sodium citrate, tartaric acid, sodium tartrate, DL-malic acid, lactic acid, DL-sodium malate; when present, the sweetener comprises at least one of: xylitol, stevioside, sucralose and maltitol.
13. The method of making an ibuprofen-containing nanosuspension according to any of claims 1 to 12, comprising the steps of:
(1) Uniformly mixing and heating all components of the oil phase component, and uniformly mixing and heating all components of the water phase component;
(2) Uniformly mixing the oil phase component and the water phase component together, and carrying out high-speed shearing emulsification treatment to obtain a primary emulsion micron-sized suspension;
(3) And (3) performing nanocrystallization treatment on the colostrum micron-sized suspension by using an ultrahigh-pressure homogenizer, and cooling to obtain the nano-suspension.
14. The method of claim 13, wherein in step (1), the oil phase ingredients are heated to 40-60 ℃; and/or heating the aqueous phase ingredients to 40-60 ℃.
15. The manufacturing method according to claim 13, wherein in the step (2), the process parameter of the high-speed shear emulsification treatment satisfies at least one of:
the temperature is 40-60 ℃;
the treatment time is 2min-8min;
the rotating speed of the high-speed shearing emulsification is 2000rpm-8000rpm.
16. The manufacturing process according to claim 13, wherein in the step (3), the nanocrystallization step includes: treating for at least 1 time by using a micro-jet ultrahigh pressure homogenizer under the pressure of 100-600 bar; treating with micro-jet ultra-high pressure homogenizer at 200-800bar for at least 1 time.
CN202211303144.5A 2022-10-24 2022-10-24 Nanometer suspension containing ibuprofen and preparation method thereof Pending CN115531311A (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113069415A (en) * 2021-04-09 2021-07-06 湖北中医药大学 Insoluble drug nanosuspension and preparation method thereof
CN113304109A (en) * 2021-06-08 2021-08-27 内蒙古大唐药业股份有限公司 A flavone acetylsalicylate solid lipid nanoparticle dispersion and its preparation method
CN115105472A (en) * 2022-07-15 2022-09-27 上海迦蓝海纳米技术集团有限公司 Nano suspension for oral mucosa administration and preparation method thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113069415A (en) * 2021-04-09 2021-07-06 湖北中医药大学 Insoluble drug nanosuspension and preparation method thereof
CN113304109A (en) * 2021-06-08 2021-08-27 内蒙古大唐药业股份有限公司 A flavone acetylsalicylate solid lipid nanoparticle dispersion and its preparation method
CN115105472A (en) * 2022-07-15 2022-09-27 上海迦蓝海纳米技术集团有限公司 Nano suspension for oral mucosa administration and preparation method thereof

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