Nasal suppository with rapid onset and long-acting retentionTechnical Field
The invention relates to a nasal mucosa administration preparation which does not depend on an adhesive and a mucosa absorption promoter, in particular to a nasal suppository which has quick acting and long acting.
Background
At present, besides injection, the quick-release preparation can be applied to clinic and has few quick-acting preparations. Injection refers to a sterile solution (including emulsions and suspensions) for Injection into the body, as prepared from a drug, and a sterile powder or concentrated solution for formulation into a solution or suspension just prior to use. The injection has the advantages of rapid and reliable action, no influence of pH, enzyme, food and the like, no first pass effect, full body or local positioning action, suitability for most patients, high injection and administration operation requirement, poor safety and organism adaptability, very difficult injection and administration for children with needle sickness and injection phobia, difficult finding of injectable veins for children with obesity and over-age, and difficult injection and administration. In addition, oral formulations generally have slow onset of action and most children have problems with oral formulations such as dysphagia.
Nasal administration is free from obvious irritation and pain, but the nasal cilia in the nasal cavity continuously transport mucus sputum adsorbed with dust and harmful bacteria to the nasopharynx through regular swing. When the nasal cilia is lowered or stops swinging due to factors such as catching cold, the nasal cilia are easy to fall off and cause nasal mucosa infection. At present, in order to increase retention time in nasal cavities and promote absorption efficiency, a certain amount of adhesive and a mucous membrane absorption promoter are needed to be added into the existing nasal cavity preparation to realize quick action and keep long-acting, and the adhesive and the mucous membrane absorption promoter can cause cilia of the nose to fall off, cause cilia toxicity and have serious adverse reactions and side effects, so the existing nasal cavity preparation is not suitable for medicines which need quick action and keep long-acting.
Suppositories (Suppository) refer to solid preparations of the drug with a suitable matrix having a shape for administration in the human body lumen. The suppository is solid at normal temperature, and can be rapidly softened and melted or dissolved in secretion at body temperature after being plugged into the cavity, and gradually releases the medicine to produce local or systemic effect. The suppository is suitable for the application of sickness, injection phobia, obesity, too small age and dysphagia of children, overcomes the problem of poor compliance of injection and oral administration, and has the characteristics that ① medicine is not damaged by gastrointestinal pH or enzyme to lose activity, ② can avoid irritation to gastric mucosa, ③ is suitable for administration at a position to avoid liver first pass effect, ④ has slow effect and is not suitable for medicines needing quick effect.
The search literature finds that the research on nasal preparations which can realize quick action and keep long-acting is not seen at present, and the report on nasal suppositories which are slow in action and large in absorption individual difference are not seen, so that the research on nasal preparations which are suitable for quick action and keep long-acting has very important application significance for overcoming needle sickness or injection fear, obesity or children with too small ages.
Disclosure of Invention
Aiming at the defects of the existing nasal preparations, the invention aims to provide a nasal suppository which is safe, efficient, quick in acting and long in acting, does not need to add an adhesive or a mucous membrane absorption promoter, has no irritation and pain, is suitable for the application of sickness, injection phobia, obesity, children with too small age and dysphagia, has a wide application range, and is particularly suitable for the treatment of water-soluble macromolecular medicaments.
The ultrasonic wave is an acoustic wave with the frequency higher than 20000 hertz (Hz), and has good directivity and strong penetrating power. At present, ultrasonic waves have been used in medicine (such as ultrasonic diagnosis, ultrasonic tooth washing, ultrasonic calculus breaking), daily life (such as air humidification, ultrasonic cleaning, ultrasonic disinfection), and the like.
Ultrasound has the effects of opening the skin barrier and promoting drug absorption. The inventor finds that the ultrasonic technology in a proper range is combined into the suppository, so that the problems of large individual absorption difference and slow effect of the existing suppository can be solved, and the suppository is prepared into a drug delivery system suitable for rapid absorption of sickness, injection phobia, obesity, oversized age and dysphagia children, thereby meeting the requirements of clinical children on rapid treatment of drugs.
Therefore, the invention provides a nasal suppository which can quickly take effect and keep long effect, the nasal suppository comprises a special suppository, an ultrasonic device, a regulating device, a power supply device, a placement and taking-out accessory, wherein the devices are combined in a modularized manner and can be detached and replaced;
the special suppository is of a hollow structure, and the shape of the special suppository can be tightly attached to the nasal passages;
The ultrasonic device comprises an ultrasonic generator and an ultrasonic probe, wherein the ultrasonic frequency emitted by the ultrasonic device is 0.1-1 MHz, and the ultrasonic intensity is 0.1-3W/cm2;
The ultrasonic probe of the ultrasonic device is suitable for being inserted into the hollow structure of the special suppository and used for conducting ultrasonic waves to contacted tissues;
The regulating device is connected with the ultrasonic device and the power supply device and is used for regulating the frequency, the intensity and the time parameters of ultrasonic waves emitted by the ultrasonic device;
the power supply device is electrically connected with the ultrasonic device and the regulating device and is used for providing electric energy required by the work of each device;
the shape of the special suppository is one of bullet shape, torpedo shape or conical shape;
the ultrasonic frequency emitted by the ultrasonic device is 0.5-1.5 MHz;
The ultrasonic frequency emitted by the ultrasonic device is 1MHz;
the intensity of the ultrasonic waves emitted by the ultrasonic device is 0.5-2W/cm2;
The intensity of the ultrasonic wave emitted by the ultrasonic device is 1W/cm2;
the ultrasonic wave emitted by the ultrasonic device is pulse ultrasonic wave;
The regulating device is connected with the ultrasonic device and the power supply device in a wired or wireless mode, and is in one of an active human regulating mode or an intelligent automatic regulating mode;
The power supply device is a disposable battery or a rechargeable battery, and the rechargeable battery is charged in a wired power supply or wireless mode.
The nasal suppository is suitable for rapidly absorbing and maintaining long-acting administration of water-soluble macromolecular drugs for children with dizziness, injection phobia, obesity, and dysphagia.
The nasal suppository which has quick action and long acting is provided with the following advantages:
1. The nasal suppository has high safety, fast acting and long acting, overcomes the problem of poor compliance of patients with injection administration and oral preparations, does not need to add an adhesive and a mucous membrane absorption promoter, has no stimulation and pain, has high safety, and is suitable for children with needle sickness, injection phobia, obesity, overage and dysphagia.
2. The nasal suppository which has the advantages of quick acting and long acting is used as the driving force for the drug to enter the mucous membrane for absorption, the high-efficiency delivery of the drug can be safely and painlessly realized, and the nasal suppository is particularly suitable for water-soluble macromolecular drugs and has high utilization rate.
3. The sustained-release nasal suppository has the advantages of quick acting and sustained-release, large contact area between the sustained-release nasal suppository and mucous membrane, uniform distribution, rapid acting speed, and high drug loading rate, and can be continuously and long-term administered, thereby having the advantage of sustained-release.
4. The operation is simple and convenient, the compliance is good, the operation requirement of injection administration is high, the operation of quick acting nasal suppository which keeps long-acting is simple and convenient, parents of children can easily operate, adult patients can realize autonomous administration without the participation of medical staff, and the nasal suppository is also applicable to patients with children, old people, mental retardation, coma and the like.
Drawings
Fig. 1 is a schematic view of a fast-acting and sustained-release nasal suppository (torpedo-shaped) structure of the present invention.
Figure 2 is a schematic illustration of a fast acting and sustained release nasal suppository (torpedo-shaped) structure of the present invention.
Detailed Description
Hereinafter, specific embodiments of the present invention will be described in detail. It should be noted that the technical features or combinations of technical features described in the following embodiments should not be regarded as being isolated, and they may be combined with each other to achieve a better technical effect.
1. As shown in fig. 1-2, the quick-acting and long-acting nasal suppository comprises a special suppository 10, an ultrasonic device 20, a regulating and controlling device 30, a power supply device 40 and a placement and extraction accessory 50, wherein the devices can be detached and replaced by adopting modularized combination, the special suppository 10 is of a hollow structure, the ultrasonic frequency emitted by the ultrasonic device 20 is 0.1-1 MHz, the ultrasonic intensity is 0.1-3W/cm2, an ultrasonic probe 21 of the ultrasonic device 20 is suitable for being inserted into the hollow structure of the special suppository 10 and used for conducting ultrasonic waves to contacted tissues, the regulating and controlling device 30 is connected with the ultrasonic device 20 and the power supply device 40 and used for adjusting frequency, intensity and time parameters of ultrasonic waves emitted by the ultrasonic device, the power supply device 40 is electrically connected with the ultrasonic device 20 and the regulating and controlling device 30 and used for providing electric energy required by the operation of the devices, the ultrasonic device is connected with the placement and extraction accessory 50 and used for placement and extraction of the nasal suppository before and after administration, and the nasal suppository has the effect of promoting quick absorption of drugs.
2. Hereinafter, specific embodiments of the present invention will be described in detail. It should be noted that the technical features or combinations of technical features described in the following embodiments should not be regarded as being isolated, and they may be combined with each other to achieve a better technical effect.
Example 1 test packet of a fast acting and sustained Long acting nasal suppository
The experimental animal is New Zealand rabbit (female), and the weight is 2-2.5 kg.
The experimental medicine is a model medicine of water-soluble macromolecular medicine and oil-soluble medicine respectively by using water-soluble fluorescent protein (molecular weight 27 kDa) and CdSe/ZnS oil-soluble quantum dots with the same fluorescent color and intensity.
The preparation of special suppository for experimental group comprises selecting matrix in table 1, heating in water bath in evaporating dish, stopping heating when 2/3 matrix is melted, stirring to melt completely, heating water-soluble matrix or oil-soluble matrix according to the requirement in table 1, adding fluorescent protein or oil-soluble quantum dot according to the method for adding medicinal composition in suppository matrix, stirring continuously to disperse medicinal composition, pouring into suppository mold coated with lubricant when the mixture is in viscous state, inserting column (to form hollow structure), cooling and solidifying, removing overflow part of the mold opening, and demolding to obtain soybean hollow suppository.
Preparation of control group purpose-built suppositories preparation according to the design of Table 1 while referring to the preparation method of the experimental group, ordinary suppositories of control groups 8 and 9 were prepared according to ordinary suppositories (without hollow structure). If the control group with the mucous membrane absorption promoter exists, the matrix is added and mixed after being heated and melted.
Animal experiment method includes the steps of firstly anaesthetizing animals, connecting each group of suppositories with an ultrasonic device, a regulating device, a power supply device (a rechargeable battery), placing and taking out accessories according to the design scheme of table 1, inserting an ultrasonic probe into a suppository hollow structure, and carrying out nasal administration on the animals, wherein the ultrasonic time is 10min.
The suppository base types of table 1 are as follows:
(1) Oil-soluble matrix, semisynthetic coco ester.
(2) Oil-soluble matrix, semisynthetic fatty acid ester.
(3) Water-soluble matrix of polyethylene glycol, polyethylene glycol 4000 (20%) and polyethylene glycol 1500 (80%).
(4) The water-soluble matrix is glycerogelatin, which comprises glycerol (65% + -5%), water (10%) and gelatin (20-30%).
The method for adding the medicine in the suppository matrix comprises the following steps:
① The oil-soluble quantum dot is prepared by dissolving oil-soluble matrix directly, or by absorbing with lanolin.
② The fluorescent protein is prepared from oleaginous matrix, small amount of water, lanolin, and water-soluble matrix through absorption and dissolving.
Mucous membrane absorption promoter, laurel nitrogenThe dosage of ketone is 0.5% of the total mass of suppository.
Table 1 experimental grouping and condition settings
Note that this set or parameter varies significantly from the parameters of the experimental group.
Example 2 test results for each set
The animals were given nasal administration according to the design of Table 1, blood was withdrawn at prescribed times of 3min, 6min and 12min, fluorescence intensity in animal blood was measured, water-soluble fluorescent protein of the same quality was dissolved in 2ml water for injection, the ear margin was intravenously injected, fluorescence intensity of fluorescent protein injection in animal blood was measured after 10min, blood-entering effect was calculated according to the following formula, then animals were sacrificed, local tissues where suppositories were located were dissected, fluorescence intensity measurement was performed in local tissues, animals were prepared into aqueous solutions with the same quality of fluorescent protein, animal body was set to-30 °, nasopharynx was blocked, local perfusion was performed for 15min, and local retention of each group of drugs in tissues was evaluated according to the following formula.
Blood-entering effect= (fluorescence intensity in blood/fluorescence intensity in blood of fluorescent protein injection for each group for a prescribed time) ×100%
Local retention = (fluorescence intensity in local tissue of suppository/fluorescence intensity after local infusion of fluorescent protein aqueous solution of each group) ×100%
The tests of each group adopt a double-blind method to overcome subjective factors, the experimental results are shown in table 2, the effect of each index in the table is expressed by a percentage (the higher the numerical value is, the better the evaluation result is), each index is synthesized, the overall evaluation of safety and effectiveness is given, and the higher the overall evaluation numerical value is, the better the comprehensive effect is represented.
Table 2 test results of each set of experiments
The results in table 2 show that the suppository indexes of the experimental group are obviously higher than those of the control group, especially the experimental groups 4 and 5, and the local retention degree and the blood-entering effect are good, so that the suppository is proved to promote the rapid absorption of the medicine. The water-soluble macromolecular drugs and the oil-soluble quantum dots of the experimental group realize rapid absorption, and prove that the method is particularly suitable for the administration of the water-soluble macromolecular drugs. In addition, the result shows that the ultrasonic penetration promoting effect is more remarkable than the drug absorption promoting effect of the mucous membrane absorption promoter, so that the auxiliary of the mucous membrane absorption promoter is not needed.
Compared with the experimental group, the suppository indexes of the control group are poor, especially the indexes of the control groups 1, 6, 8 and 9 are worst, and the indexes of the control groups 3 and 4 are good, but the experimental animals are agitation, so that the related parameters are proved to cause stimulation reaction, and the suppository is not suitable for being applied to human bodies. The index of the control group 7 is good, but the ultrasonic parameters cannot be regulated in time, and a regulation device is proved to be indispensable.
The results in table 2 prove that any device component and parameters thereof in the technical protection scheme of the nasal suppository, which can quickly take effect and keep long-acting, are mutually synergistic and indispensable, and the lack of any device component and parameters thereof in the technical protection scheme of the invention can greatly influence the blood-entering effect of the medicament. The nasal suppository which has the advantages of quick action, long acting maintenance, safety, high efficiency and convenient application has good application prospect.