CN108096408A - A kind of nasal spray and its preparation and application - Google Patents

Abstract

The invention relates to a spray, and discloses a preparation method and application of a nasal spray containing plant essential oil submicroemulsion. Its raw materials and quality components are: plant essential oil 0.6%-3%, oil phase 4.4%-12%, tween-80 0.8%-6.5%, short-chain alcohol 0.5%-5%, ethanol 0.5%-4.5%, vitamin E0.05% to 2%, preservatives 0.25% to 1%, the balance of sterile water. The plant essential oil submicron emulsion spray has a simple preparation process, is convenient for industrial production, has good antibacterial and antibacterial activities, high bioavailability and no drug dependence, and can protect and moisturize the nasal cavity in polluted conditions and dry environments. It has a good preventive and relieving effect on rhinitis, sinusitis, allergic rhinitis and other diseases.

Description

A kind of nasal spray and its preparation and application

technical field

The invention relates to the field of medicine and health care products, in particular to a preparation method and application of a nasal spray containing plant essential oil submicron emulsion. The plant essential oil submicron emulsion spray has a simple preparation process, is convenient for industrial production, has good antibacterial and antibacterial activity on fungi in the nasal cavity, has no drug dependence, and protects and moisturizes the nasal cavity in polluted conditions and dry environments. It can prevent and alleviate the occurrence and symptoms of rhinitis, sinusitis, allergic rhinitis and other diseases.

Research Background

With the rapid development of my country's industrialization, urbanization and other processes, air pollution in key areas, especially the pollution of fine particulate matter PM2.5, has become normalized and exceeded the standard. Numerous studies have shown that atmospheric fine particulate matter PM2.5 can induce allergic rhinitis, bronchial asthma and other respiratory diseases and aggravate their symptoms (Abbery DE, Ostro BE, Petersen F, et al. Chronic respiratory symptoms associated with estimated long-term ambient concentrations of fine particulates less than 2.5microns in aerodynamic dimmeter(PM2.5) and other air pollution, J Exposure Analy Envir Epide,5(2):137-159,1995.).

In view of the increasingly severe environmental pollution problems, the number of patients with respiratory diseases, especially rhinitis, allergic rhinitis, and asthma, will increase significantly. The respiratory system drug market will continue to grow in the future and has become a key area of pharmaceutical research and development. One of (Straif K, Cohen A, Samet J. Air pollution and Cancer, International Agency for Research on Cancer Scientific Publication, 2013). Taking allergic rhinitis as an example, the incidence of allergic rhinitis in Asia is relatively high, about 30% of adults suffer from this disease, and it is as high as 36% in northern my country. Kapsali et al. found that allergic rhinitis has a very close relationship with asthma, and the former is one of the important factors that induce asthma. About 60%-80% of patients with allergic rhinitis can develop asthma (Kapsali, T et al. Rhinitis is ubiquitous in allergic asthmatics, Journal of allergy and clinical immunology, 1997, 99(1):556-556).

Allergic rhinitis is a controllable common respiratory disease. The current treatment methods mainly include drug therapy and surgical treatment, among which drug therapy is the first choice. At present, the treatment of respiratory diseases such as allergic rhinitis is mostly aimed at the relief and control of symptoms. Commonly used drug treatments include antihistamines (such as chlorpheniramine), decongestants (such as furama nasal drops), glucocorticoids (such as budesonide), etc., which can effectively control and relieve symptoms. However, the drug treatment generally does not exceed 7 days, and long-term medication can cause drug-induced rhinitis or drug dependence, and the side effects are large.

Drug administration methods for allergic rhinitis and other diseases are roughly divided into inhalation administration, oral administration, mucosal administration, etc. Among them, inhalation administration is currently recognized as the preferred method of administration for the prevention and treatment of asthma, rhinitis and other respiratory diseases. The most effective and safest therapy. Compared with other drug delivery methods, inhalation drug delivery has the advantages of rapid absorption, high bioavailability, less side effects, quick onset of action, and convenient use. Since Riker Laboratories (now 3M Pharmaceuticals) developed the world's first product in 1956, inhalants have a development history of more than 60 years.

Nasal spray refers to a preparation that does not contain a propellant and releases the contents into the nasal cavity in the form of mist with the help of manual pump pressure, and the drug is absorbed through the nasal mucosa to exert local or systemic effects. Compared with nasal drops, spray administration can make the dispersion and distribution area of the drug in the nasal mucosa wider; compared with aerosol, it overcomes the irritation and side effects of propellants such as Freon on the nasal mucosa.

Natural essential oils are unique aromatic substances extracted from flowers, rhizomes, leaves, fruits, seeds and other parts of plants. They have high volatility, low molecular weight, easy penetration through cell membranes, and have natural antibacterial, antiviral, antioxidative and other biological activities. , long-term use without side effects, widely used in medicine, beauty care products and food processing and other fields. The absorption of the nasal mucosa is considered to be a passive absorption process. The molecular weight is less than 1000, and the highly fat-soluble substances are easily absorbed through the cell membrane. By up-regulating the expression of catalase, glutathione reductase, superoxide dismutase, etc. to up-regulate the gene pathways of anti-oxidation and anti-inflammation, and by reducing the levels of IgE, NK-kappa B and AP-1 in serum Inhibit or reduce the occurrence of pro-inflammatory reactions (XiChen, et al.Curcumol exhibits anti-inflammatory properties by interfering with the JNK-mediated AP-1 pathway in lipopolysaccharide-activated RAW264.7 cells, European Journal of Pharmacology, 2014, 723 (15 ):339-345). Therefore, natural essential oils are ideal active ingredients for nasal sprays.

The invention selects natural plant essential oil as an active substance, supplements with excipients to make a submicroemulsion nasal cavity spray for preventing and treating allergic rhinitis. The spray has many advantages such as uniform drug dispersion, rapid local onset, direct action on the lesion, stable dose, no drug dependence, no toxic and side effects, easy to carry and can be used for many times.

Contents of the invention

The purpose of the present invention is to provide a preparation method and application of a nasal spray containing plant essential oil submicroemulsion.

The present invention is characterized in that comprising following raw material and mass percentage:

Plant essential oil 0.6%～3%

Oil phase 4.4%～12%

tween-80 0.8%～6.5%

Short chain alcohol 0.5%～5%

Ethanol 0.5%～4.5%

Vitamin E0.05%～2%

Preservatives 0.25%～1%

water balance.

Above-mentioned spray, it is characterized in that: described plant essential oil is sweet orange oil, clove oil, turpentine, menthol, clove oil, bergamot oil, litsea cubeba oil, citronella oil, rosemary oil, thyme oil , absinthe oil, cinnamon oil or chamomile oil, etc. or a mixture of two or more.

The above-mentioned spray is characterized in that: the oil phase is refined soybean oil, perilla seed oil, corn oil, coconut oil, olive oil, jojoba oil, castor oil, evening primrose oil, perilla seed oil, etc. One or two or more of the medicinal oil phases are mixed.

The above-mentioned spray is characterized in that: the short-chain alcohol is one or more of glycerin, 1,2-propanediol and 1,3-propanediol.

The above-mentioned spray is characterized in that: the preservative is one or more of parabens, benzoic acids and sorbic acids.

The preparation method of any one of the above-mentioned nasal sprays containing plant essential oil microemulsion has the following steps:

(1) Select medicinal grade plant essential oil, oil phase, tween-80, short-chain alcohol, ethanol, vitamin E, preservative, water as raw materials, and the mass percentage of each raw material in total weight is 0.6% to 3% of plant essential oil , oil phase 4.4%~12%, tween-800.8%~6.5%, short chain alcohol 0.5%~5%, ethanol 0.5%~4.5%, vitamin E 0.05%~2%, preservative 0.25%~1%, Sterile water balance;

(2) dissolving plant essential oil and vitamin E in the oil phase under room temperature conditions to make an oil phase mixture;

(3) Dissolve tween-80, short-chain alcohols, ethanol, and preservatives in sterile water at room temperature to prepare a water phase mixture;

(4) At room temperature, under magnetic stirring, the oil phase mixture is slowly added dropwise to the water phase mixture to produce colostrum;

(5) Cut the colostrum in a high-shear homogenizer for 2 to 5 times, each time for 3 to 5 minutes to prepare the essential oil submicron emulsion;

(6) Submicron emulsion obtained in step (5) is subpackaged and sealed.

The above-mentioned preparation method is characterized in that: the preparation of the oil-phase mixed liquid in step (2) is completed in a closed container under the condition of magnetic stirring, the stirring speed is 800-1200 rpm, and the stirring time is 10-40 minutes.

The above preparation method is characterized in that: the preparation of the aqueous phase mixture in step (3) is completed under the condition of magnetic stirring, the stirring speed is 500-1000 rpm, and the stirring time is 10-30 min.

The above-mentioned preparation method is characterized in that: in step (4), the stirring speed is 1000-1500 rpm, and after the oil phase is added to the aqueous phase solution, it is sealed and stirred for 20-60 min.

The above-mentioned preparation method is characterized in that: in step (5), the rotational speed of the high-shear homogenizer is 15,000-30,000 rpm.

The plant essential oil submicron emulsion spray has a simple preparation process, is convenient for large-scale production, has good antibacterial and antibacterial activity on fungi in the nasal cavity, high bioavailability and drug dependence; it can protect the nasal cavity in polluted conditions or dry environments And moisturizing effect, as a preventive or relieving preparation for rhinitis, sinusitis, or allergic rhinitis.

The present invention has the following advantages:

1. Natural plant essential oils are active small molecules and volatile substances, which can easily pass through the nasal mucosa barrier to exert antibacterial and anti-inflammatory effects.

2. Compared with existing drugs for treating allergic rhinitis and asthma, the main components of the present invention are derived from natural plants, have high biological activity, are safe and effective, have no drug dependence, do not cause drug-induced rhinitis, and can be used for many times for a long time. Both preventive and therapeutic purposes.

3. Preparation The preparation process is green and environmentally friendly, and the process is simple and easy to scale up in pilot scale.

Detailed ways

The present invention will be described in detail below in conjunction with specific embodiments. The following examples will help those skilled in the art and researchers to further understand the present invention, but do not constitute any limitation to the present invention. Any form of modification made by anyone within the scope of the claims of the present invention is still within the scope of the claims of the present invention.

Example 1

(1) Take medicinal raw materials according to the following mass ratios:

(2) Preparation method: Add the weighed sweet orange oil, clove basil oil, lemon oil, rosemary oil, and vitamin E to the mixed oil of perilla seed oil and coconut oil drop by drop, stir at 800rpm for 20min under airtight conditions, and mix Obtain oil phase solution A evenly. Dissolve tween-80, ethanol, glycerol, and methylparaben in water to prepare aqueous phase mixture B. At room temperature, add A to B dropwise at 1200 rpm, and stir for 30 minutes to obtain milk. Use a high-shear milk homogenizer to stir the colostrum at room temperature at high speed, at a speed of 15,000 rpm for 3 minutes, and repeat the cycle 3 times. After packaging and sealing, the essential oil submicron emulsion nasal spray with uniform dispersion and uniform particle size is obtained.

(3) In vitro antibacterial test results

Example 2

(1) Take medicinal raw materials according to the following mass ratios:

(2) Preparation method: Add the weighed sweet orange oil, clove basil oil, lemon oil, rosemary oil, and vitamin E dropwise into the mixed oil phase of perilla seed oil and corn germ oil, and stir at 1000rpm for 30min under airtight conditions , and mix uniformly to obtain oil phase solution A. Dissolve tween-80, ethanol, 1,2-propanediol, and ethylparaben in water to prepare aqueous phase mixture B. At room temperature, add A to B dropwise at 1000 rpm, and stir for 30 minutes to obtain colostrum. Use a high-shear homogenizer to stir the colostrum at room temperature at a high speed, at a speed of 20,000 rpm for 5 minutes, and repeat 3 times. After packaging and sealing, the essential oil submicron emulsion nasal spray with uniform dispersion and uniform particle size is obtained.

Example 3

(1) Take medicinal raw materials according to the following mass ratios:

(2) Preparation method: Add the weighed sweet orange oil, lemon oil, peppermint oil and vitamin E dropwise into the mixed oil phase of castor oil, olive oil and refined soybean oil, stir at 1000rpm for 20min under airtight conditions, and mix evenly to obtain Oil phase solution A. Dissolve tween-80, ethanol, 1,3-propanediol, and sorbitol in water to prepare aqueous phase mixture B. At room temperature, add A to B dropwise at 1500 rpm, and stir for 30 minutes to obtain colostrum. Use a high-shear milk homogenizer to stir the colostrum at room temperature at high speed, 25,000 rpm for 5 minutes, and repeat 3 times. After packaging and sealing, the essential oil submicron emulsion nasal spray with uniform dispersion and uniform particle size is obtained.

Example 4

Select 4 New Zealand big-eared whites, prepare their skins, use their own left and right side comparison method, and use the nasal spray prepared in Example 1 according to the skin irritation test requirements issued by the National Experimental Drug Administration, and the reference preparation is sterile normal saline.

Multiple administrations at the same site were used for 1-2 consecutive weeks, and the irritation intensity was evaluated with reference to the skin irritation reaction scoring standard.

The results showed that none of the 4 experimental animals had erythema, no edema and no appearance. There was no significant difference between the mean values of the experimental group and the control group. The nasal spray obtained by the present invention has no skin irritation.

Example 5

Select 10 SD rats weighing 200±2g, half male and half male, and randomly divide them into experimental group and control group, with 5 rats in each group. The experimental group is the nasal spray prepared in Example 2, and the control group is sterile physiological saline.

The experimental conditions were at room temperature. Each group of rats was quantitatively instilled with 40 μL of spray or normal saline to the right nose through a pipette each time. When administering, the rats were fixed in a lateral or supine position and kept until 5 minutes after administration. Administer 3-5 times a day. Record the local irritation symptoms of rats, such as runny nose, scratching nose and other symptoms or actions. After 14 days of continuous administration, the rats were sacrificed by dislocation, the nasal cavity was cut open immediately, and the congestion and edema of the nasal mucosa were observed after washing with PBS. Grading and scoring were carried out according to the grading standard of local mucosal irritation reaction. The experimental data were statistically analyzed by one-way analysis of variance.

The results showed that after administration, the animals in both the control group and the experimental group had symptoms or actions such as runny nose, nose scratching, and sneezing. There was no significant difference in the time and frequency of the two groups. Stimulus response score results: normal saline group = 0.24 ± 0.17, experimental group = 0.37 ± 0.15, no significant difference between the two groups.

Example 6

Select 20 Kunming mice, half male and half female, weighing 22±5g, and randomly divide them into 4 groups, 5 mice in each group, which are respectively the normal saline control group and the nasal spray experimental group prepared in Examples 1, 2, and 3.

The administration dose was 2 μL/10g body weight, and each mouse was administered 3 times at the same time every day with an interval of 4 hours, and the administration was continued for 7 days. After the last administration, each mouse was sensitized by smearing 20 μL of xylene on the inside and outside of the left auricle, and the right ear on the same side was used as a control. After 30 minutes of sensitization, the mice were sacrificed by dislocation, and holes were punched in the same part of both ears with a puncher, and weighed. The swelling degree was expressed by the difference in the left and right ear weights, and the swelling degree and inhibition rate of each group were calculated, and the inhibition rate=(the swelling degree of the control group-the swelling degree of the experimental group)/the swelling degree of the control group×100%. The experimental data were statistically analyzed by one-way analysis of variance.

The results are shown in Table 1 below. Compared with the control group, each experimental group has a different degree of swelling inhibition effect and the results are significantly different (p<0.05).

Table 1 Effect of plant essential oil spray on mouse ear swelling

Note: * means p<0.05

Example 7

Select 20 Kunming mice, half male and half female, weighing 22±5g, and randomly divide them into 4 groups, 5 mice in each group, which are respectively the normal saline control group and the nasal spray experimental group prepared in Examples 1, 2, and 3.

The administration dose was 2 μL/10g body weight, and each mouse was administered 3 times at the same time every day with an interval of 4 hours, and the administration was continued for 7 days. 30 minutes after the last administration, each mouse was injected with 0.2 mL of Staphylococcus aureus solution (concentration: 3.5×10 ¹⁰ /mL), once 8 hours after the injection, and the dosage remained unchanged. The death of mice was observed for 48h and the death rate was calculated. The experimental data were analyzed by one-way analysis of variance. The results are shown in Table 2 below.

Table 2 Protective effect of plant essential oil spray on mice infected with Staphylococcus aureus

Note: * means p<0.05.

Claims (9)

1. a kind of nasal spray, which is characterized in that including following raw materials according and mass percent：

Plants essential oil 0.6%~3%

Oil phase 4.4%~12%

Tween-80 0.8%~6.5%

Short chain alcohol 0.5%~5%

Ethyl alcohol 0.5%~4.5%

Vitamin E 0.05%~2%

Preservative 0.25%~1%

Water surplus.

2. spray according to claim 1, which is characterized in that the plants essential oil is orange oil, cloves enumerates oil, pine Fuel-economizing, menthol, caryophyllus oil, bergamot oil, litsea citrate oil, citronella oil, rosemary oil, thyme oil, absinthium, cassia oil or One or two or more kinds of mixing in oil of chamomile etc..

3. spray according to claim 1, which is characterized in that the oil phase is refined soybean oil, Purple Perilla Seed Oil, corn One kind in the medicinal oil phase such as oil, coconut oil, olive oil, SIMMONDSIA CHINENSIS SEED OIL, castor oil, evening primrose oil, Purple Perilla Seed Oil or two kinds with Upper mixing.

4. spray according to claim 1, which is characterized in that the short chain alcohol is glycerine, 1,2-PD and 1,3 third The one or two or more kinds of glycol.

5. spray according to claim 1, which is characterized in that the preservative is oxybenzene esters, benzoic acids and mountain One or two or more kinds in pears acids.

6. a kind of preparation method of any nasal sprays of claim 1-5, it is characterised in that：

(1) it is raw material to choose pharmaceutical grade plants essential oil, oil phase, tween-80, short chain alcohol, ethyl alcohol, vitamin E, preservative, water, The mass percent that each raw material accounts for gross weight is respectively plants essential oil 0.6%~3%, oil phase 4.4%~12%, tween-80 0.8%~6.5%, short chain alcohol 0.5%~5%, ethyl alcohol 0.5%~4.5%, vitamin E 0.05%~2%, preservative 0.25%~1%, sterile water surplus；

(2) plants essential oil, vitamin E are dissolved in oil phase under room temperature, oil phase mixed liquor is made；

(3) tween-80, short chain alcohol, ethyl alcohol, preservative are dissolved in sterile water under room temperature, water is made and mixes liquid；

(4) oil phase mixed liquor is slowly added dropwise under magnetic agitation and mixes liquid into water, colostrum is made by room temperature；

(5) by colostrum high shear dispersing emulsification machine shear 2-5 times, every time 3~5min essential oil Submicron Emulsion is made；

(6) Submicron Emulsion obtained by step (5) is dispensed, sealing.

7. preparation method according to claim 6, which is characterized in that oil phase mixed liquor is closed in the step (2) It in container, is prepared under the conditions of magnetic agitation, 800~1200rpm of mixing speed, 10~40min of mixing time；

Water mixes the preparation of liquid and completes under the conditions of magnetic agitation in the step (3), and 500~1000rpm of mixing speed is stirred Mix 10~30min of time；

1000~1500rpm of mixing speed in the step (4), after oil phase adds in aqueous phase solution, 20~60min of closed stirring.

8. preparation method according to claim 6, which is characterized in that high shear dispersing emulsification machine rotating speed is in the step (5) 15000~30000rpm.

9. a kind of application of any nasal sprays of claim 1-5, it is characterised in that：The nasal spray can be to dirt Nasal cavity plays protection and wetting action in dye condition or dry environment, as the prevention to rhinitis, nasosinusitis or allergic rhinitis Or Seed-coat-agents.