Controlled-release ultrasonic rectal suppository

Abstract

The controlled release type ultrasonic rectal suppository comprises a specially-made suppository, an ultrasonic device, a regulation and control device, a power supply device and placing and taking-out accessories, and all the devices are modularly combined and can be detached and replaced. The controlled-release ultrasonic rectal suppository disclosed by the invention is suitable for children with faint of acupuncture, injection phobia, obesity and too low age, has no stimulation and pain sensation, is wide in applicable drug range, is particularly suitable for water-soluble macromolecular drugs, does not need to add a mucous membrane absorption enhancer, overcomes the defects of large difference of absorption individuals and slow effect of the conventional suppository administration, and is suitable for clinical application. The effect of promoting rapid absorption of the medicine is achieved.

Description

Technical Field

[0001] The present invention relates to a drug delivery preparation for rapid rectal mucosal absorption independent of a mucosal absorption promoter, in particular to a controlled-release ultrasonic rectal suppository. Background Art

[0002] Injection refers to sterile solutions (including emulsions and suspensions) made of drugs for injection into the body, as well as sterile powders or concentrated solutions for preparation into solutions or suspensions before clinical use. Injections act quickly and reliably, are not affected by pH, enzymes, food, etc., have no first-pass effect, can exert systemic or local positioning effects, and are suitable for most patients. However, injection administration requires high operation requirements, and has poor safety and body adaptability. For children with needle phobia and injection phobia, injection administration is very difficult. For obese and young children, it is not easy to find a vein for injection, and there is also the problem of difficulty in administration.

[0003] Suppository refers to a solid preparation with a certain shape made of drugs and suitable matrix for administration into human cavities. Suppositories are solid at room temperature. After being inserted into the cavity, they can quickly soften, melt or dissolve in the secretion fluid at body temperature, gradually releasing the drug to produce local or systemic effects. Suppositories have the following characteristics: ① The drug is not destroyed by gastrointestinal pH or enzymes and loses its activity; ② Drugs that are irritating to the gastric mucosa can be administered rectally and avoid irritation; ③ The drug is absorbed by the middle and lower rectal veins to avoid the first-pass effect of the liver; ④ There are few interference factors for rectal absorption; ⑤ There is no obvious irritation or pain.

[0004] Suppositories are suitable for infants and children because they do not cause obvious irritation or pain. However, there are large individual differences in the absorption of suppositories, and the onset of action is slow, especially for water-soluble macromolecular drugs. Even if mucosal absorption enhancers are added, they cannot promote rapid absorption of the drug. Mucosal absorption enhancers are used in large quantities and have safety risks. Therefore, existing suppositories are not suitable for drugs that need to take effect quickly.

[0005] A literature search revealed that there has been no research to improve the problems of large individual differences in suppository absorption and slow onset of action, and there has been no report on a new type of suppository that solves these problems. Therefore, the development of controlled-release suppositories suitable for children is of great application significance in overcoming the fear of needles or injections, obesity or the treatment of very young children.

[0006] In short, the existing injections cannot meet the treatment needs of children with needle phobia or injection phobia, obesity or too young, while the existing suppositories have problems of large individual differences in absorption and slow onset of action, especially water-soluble macromolecular drugs are absorbed slowly and need to be added with mucosal absorption promoters, which poses a safety hazard. At present, there is no drug delivery system suitable for children with needle phobia, injection phobia, obesity and too young that can control the release of absorption without relying on mucosal absorption promoters, which greatly limits the application of clinical pediatric drug treatment. Summary of the invention

[0007] The purpose of the present invention is to provide a safe and efficient controlled-release ultrasonic rectal suppository, which is suitable for children with needle phobia, injection phobia, obesity and too young age, has no irritation and pain, is applicable to a wide range of drugs, is particularly suitable for water-soluble macromolecular drugs, does not require the addition of a mucosal absorption promoter, and overcomes the shortcomings of existing suppositories such as large individual differences in absorption and slow onset of effect.

[0008] Ultrasound is a sound wave with a frequency higher than 20,000 Hz. It has good directionality and strong penetrating power. At present, ultrasound has many applications in medicine (such as ultrasonic diagnosis, ultrasonic tooth cleaning, ultrasonic stone crushing) and daily life (such as air humidification, ultrasonic cleaning, ultrasonic disinfection).

[0009] Ultrasound has the function of opening the skin barrier and promoting drug absorption. The inventors have found that by combining ultrasound technology within an appropriate range into suppositories, the problems of large individual differences in absorption and slow onset of action of existing suppositories can be overcome, and a drug delivery system suitable for children with needle phobia, injection phobia, obesity, and too young children with rapid absorption can be prepared, thereby meeting the needs of clinical children's rapid drug treatment.

[0010] Therefore, a controlled-release ultrasonic rectal suppository is invented, which comprises: a specially prepared suppository, an ultrasonic device, a regulating device, a power supply device, and placement and removal accessories, wherein each device is modularly combined and can be disassembled and replaced;

[0011] The above-mentioned special suppository is a hollow structure, and its appearance is a shape that can fit closely with the rectal cavity;

[0012] The ultrasonic device comprises an ultrasonic generator and an ultrasonic probe. The ultrasonic frequency emitted by the ultrasonic device is 0.5-3 MHz and the ultrasonic intensity is 0.1-5 W / cm 2 ;

[0013] The ultrasonic probe of the ultrasonic device is suitable for being inserted into the hollow structure of the special suppository to transmit ultrasonic waves to the contacted tissue;

[0014] The above-mentioned control device is connected to the ultrasonic device and the power supply device, and is used to adjust the frequency, intensity and time parameters of the ultrasonic waves emitted by the ultrasonic device;

[0015] The power supply device is electrically connected to the ultrasonic device and the control device to provide the electrical energy required for the operation of each device; the ultrasonic rectal suppository has the effect of promoting rapid absorption of drugs;

[0016] The shape of the special suppository is one of a bullet shape, a torpedo shape or a cone shape;

[0017] The ultrasonic frequency emitted by the above-mentioned ultrasonic device is 1 to 2 MHz;

[0018] The ultrasonic frequency emitted by the above-mentioned ultrasonic device is 1.5MHz;

[0019] The ultrasonic wave intensity emitted by the above ultrasonic device is 0.5~3W / cm 2 ;

[0020] The ultrasonic intensity emitted by the above-mentioned ultrasonic device is 1.5W / cm 2 ;

[0021] The ultrasonic wave emitted by the above-mentioned ultrasonic device is a pulsed ultrasonic wave;

[0022] The control device is connected to the ultrasonic device and the power supply device by wire or wireless means, and the control device is one of a human active control mode and an intelligent automatic control mode;

[0023] The power supply device is a disposable battery or a rechargeable battery, and the rechargeable battery is charged by wired power supply or wirelessly.

[0024] The ultrasonic rectal suppository is suitable for rapid absorption and administration of water-soluble macromolecular drugs to children who are needle-sick, injection-phobic, obese or too young.

[0025] The controlled-release ultrasonic rectal suppository of the present invention has the following advantages:

[0026] 1. High safety: Controlled-release ultrasonic rectal suppositories overcome the shortcomings of injection administration, such as poor safety and poor body adaptability. It is very difficult to administer injections to children with needle phobia, injection phobia, obesity, and too young children. There is no need to add mucosal absorption enhancers, and it is highly safe.

[0027] 2. High drug utilization rate: The controlled-release ultrasonic rectal suppository of the present invention uses ultrasound as the driving force for the drug to enter the mucosa for absorption, which can achieve efficient drug release safely and painlessly, is particularly suitable for water-soluble macromolecular drugs, and has a high utilization rate.

[0028] 3. It has the dual advantages of rapid onset of action and long-term effect: the controlled-release ultrasonic rectal suppository has a large and evenly distributed contact area with the mucosa, which accelerates drug absorption to the maximum extent and has a fast onset of action; at the same time, the suppository has a large drug load and can be administered continuously for a long time, so it has the advantage of maintaining long-term effect.

[0029] 4. Easy to operate and good compliance: The operation requirements of injection administration are high, while the controlled-release ultrasonic rectal suppository is easy to operate. It is easy for parents of children to operate, and adult patients can achieve self-administration without the participation of medical staff. It is also applicable to children, the elderly, mentally retarded, comatose patients, etc. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 A schematic structural diagram of the controlled-release ultrasonic rectal suppository (torpedo-shaped) of the present invention.

[0031] Figure 2 A schematic structural diagram of the controlled-release ultrasonic rectal suppository (torpedo-shaped) of the present invention. DETAILED DESCRIPTION

[0032] The specific embodiments of the present invention will be described in detail below. It should be noted that the technical features or combinations of technical features described in the following embodiments should not be considered isolated, and they can be combined with each other to achieve better technical effects.

[0033] 1. As Figures 1-2 As shown, the controlled-release ultrasonic rectal suppository of the present invention comprises: a special suppository 10, an ultrasonic device 20, a regulating device 30, a power supply device 40, and a placement and removal accessory 50. The devices are modularly combined and can be disassembled and replaced. The special suppository 10 is a hollow structure. The ultrasonic device 20 emits an ultrasonic frequency of 0.5 to 3 MHz and an ultrasonic intensity of 0.1 to 5 W / cm 2 The ultrasonic probe 21 of the ultrasonic device 20 is suitable for being inserted into the hollow structure of the special suppository 10, and is used to transmit ultrasonic waves to the contacted tissue; the regulating device 30 is connected with the ultrasonic device 20 and the power supply device 40, and is used to adjust the frequency, intensity and time parameters of the ultrasonic waves emitted by the ultrasonic device; the power supply device 40 is electrically connected with the ultrasonic device 20 and the regulating device 30, and is used to provide the electric energy required for the operation of each device; the ultrasonic device is connected with the placement and removal accessory 50, and is used for the placement and removal of the ultrasonic rectal suppository before and after administration; the ultrasonic rectal suppository has the effect of promoting the rapid absorption of drugs.

[0034] 2. The specific embodiments of the present invention will be described in detail below. It should be noted that the technical features or combinations of technical features described in the following embodiments should not be considered isolated, and they can be combined with each other to achieve better technical effects.

[0035] Example 1 Test Grouping of Controlled Release Ultrasonic Rectal Suppositories

[0036] Experimental animals: New Zealand rabbits (female), weighing 2-2.5 kg.

[0037] Experimental drugs: Water-soluble fluorescent protein (molecular weight 27 kDa) and CdSe / ZnS oil-soluble quantum dots with the same fluorescence color and intensity were used as model drugs for water-soluble macromolecular drugs and oil-soluble drugs, respectively.

[0038] Preparation of special suppositories in the experimental group: divided into experimental group and control group according to the design in Table 1, select the matrix in Table 1, place it in an evaporating dish and heat it in a water bath, stop heating when 2 / 3 of the matrix is ​​melted, and stir to make it completely melted; heat and melt the water-soluble matrix or oil-soluble matrix according to the requirements of Table 1, and then add fluorescent protein or oil-soluble quantum dots according to the "method of adding drugs to suppository matrix", stir continuously to make the drug evenly dispersed, and when the mixture is viscous, pour it into the suppository mold coated with lubricant, insert the column (to form a hollow structure), pull out the column after cooling and solidification, cut off the overflow part on the mold mouth, demold, and make a hollow suppository the size of a soybean for use.

[0039] Preparation of special suppositories for the control group: Prepare according to the design scheme in Table 1 and refer to the preparation method of the experimental group. Ordinary suppositories for control groups 8 and 9 are prepared according to ordinary suppositories (without hollow structure). If there is a control group with mucosal absorption enhancer, add it after the matrix is ​​heated and melted and mix well.

[0040] Animal experimental method: Each group of animals was first anesthetized, and then the suppositories of each group were connected to the ultrasound device, the control device, the power supply device (rechargeable battery), the placement and removal accessories according to the design scheme in Table 1. The ultrasound probe was inserted into the hollow structure of the suppository, and the animal rectal administration was performed. The ultrasound time was 10 minutes.

[0041] The suppository base types of Table 1 are as follows:

[0042] (1) Oil-soluble matrix: semi-synthetic coconut oil ester.

[0043] (2) Oil-soluble matrix: semi-synthetic fatty acid esters.

[0044] (3) Water-soluble matrix: polyethylene glycol: polyethylene glycol 4000 (20%) and 1500 (80%).

[0045] (4) Water-soluble matrix: glycerol gelatin: glycerol (65% ± 5%), water (10%) and gelatin (20-30%).

[0046] Method of adding drugs to suppository matrix:

[0047] ① Oil-soluble quantum dots: If it is an oily matrix, add it directly to dissolve it; if it is a water-soluble matrix, absorb it with an appropriate amount of lanolin and then add it.

[0048] ② Fluorescent protein: If it is an oily matrix, add a small amount of water and add it after absorbing it with an appropriate amount of lanolin; if it is a water-soluble matrix, add it directly to dissolve it.

[0049] Mucosal absorption enhancer: lauryl nitrogen Ketone, the amount is 0.5% of the total mass of the suppository.

[0050] Table 1 Experimental groups and condition settings

[0051]

[0052] Note: * indicates that the setting or parameter has significant changes compared with the parameters of the experimental group.

[0053] Example 2 Test results of each group

[0054] Each group of animals was given rectal administration according to the design in Table 1, and blood was drawn at the specified time of 3min, 6min and 12min, and the fluorescence intensity in the blood of the animals was detected. Another animal was selected to dissolve the same mass of water-soluble fluorescent protein in 2ml of water for injection and injected into the ear vein. After 10min, the fluorescence intensity of the fluorescent protein injection in the blood of the animals was detected, and the blood entry effect was calculated according to the following formula; then the animals were killed, the local tissue where the suppository was located was dissected, and the fluorescence intensity in the local tissue was detected. Another animal was selected to prepare an aqueous solution of the same mass of fluorescent protein, which was locally perfused, and the fluorescence intensity was detected after 15min. The local retention degree of each group of drugs in the tissue was evaluated according to the following formula.

[0055] Blood entry effect = (fluorescence intensity in the blood of each group at a specified time / fluorescence intensity in the blood of the fluorescent protein injection) × 100%

[0056] Local retention degree = (fluorescence intensity in local tissue of each group of suppositories / fluorescence intensity after local perfusion of fluorescent protein aqueous solution) × 100%

[0057] The test of each group adopted the double-blind method to overcome subjective factors. The experimental results are shown in Table 2. The effect of each indicator in the table is expressed as "percentage" (the higher the value, the better the evaluation result). The overall evaluation of safety and effectiveness is given by combining various indicators. The higher the overall evaluation value, the better the overall effect.

[0058] Table 2 Test results of each group of experiments

[0059]

[0060] The results in Table 2 show that the various indicators of the suppositories in the experimental group are significantly higher than those in the control group, especially in experimental groups 4 and 5, with good local retention and blood entry effects, proving that it promotes rapid drug absorption. The water-soluble macromolecular drugs and oil-soluble quantum dots in the experimental group were both rapidly absorbed, proving that the method of the present invention is particularly suitable for the administration of water-soluble macromolecular drugs. In addition, the results show that the ultrasonic permeation effect is more significant than the drug absorption effect of the mucosal absorption enhancer, so the assistance of the mucosal absorption enhancer is not required.

[0061] Compared with the experimental group, the suppository index of the control group was poor, especially the indexes of control groups 1, 6, 8 and 9 were the worst. Although the indexes of control groups 3 and 4 were good, the experimental animals were agitated, proving that the relevant parameters caused irritation and were not suitable for human application. The indexes of control group 7 were good, but the ultrasonic parameters could not be adjusted in time, proving that the control device was indispensable.

[0062] The results in Table 2 prove that any device component and its parameters in the technical protection scheme of the controlled-release ultrasonic rectal suppository of the present invention are mutually coordinated and indispensable. The lack of any device component and its parameters in the technical protection scheme of the present invention will have a greater impact on the blood entry effect of the drug. The controlled-release ultrasonic rectal suppository of the present invention is safe, efficient, and easy to use, and has a good application prospect.

Claims

1. A controlled release ultrasonic rectal suppository, characterized in that: The controlled-release ultrasonic rectal suppository comprises: a special suppository, an ultrasonic device, a regulating device, a power supply device, and placement and removal accessories. The devices are modularly combined and can be disassembled and replaced. The special suppository is a hollow structure, and its shape is a shape that can fit closely with the rectal cavity. The ultrasonic device comprises an ultrasonic generator and an ultrasonic probe. The ultrasonic device emits an ultrasonic frequency of 0.5 to 3 MHz and an ultrasonic intensity of 0.1 to 5 W / cm 2 The ultrasonic probe of the ultrasonic device is suitable for being inserted into the hollow structure of the special suppository, and is used to transmit ultrasonic waves to the contacted tissue; the regulating device is connected with the ultrasonic device and the power supply device, and is used to adjust the frequency, intensity and time parameters of the 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 to provide the electric energy required for the operation of each device; the ultrasonic device is connected with the placement and removal accessories, and is used for the placement and removal of the ultrasonic rectal suppository before and after administration; the ultrasonic rectal suppository does not need to add a mucosal absorption promoter, and has the effect of promoting rapid absorption of drugs.

2. The controlled release ultrasonic rectal suppository according to claim 1, characterized in that: The shape of the special suppository is one of a bullet shape, a torpedo shape or a cone shape.

3. The controlled release ultrasonic rectal suppository according to claim 1, characterized in that: The ultrasonic frequency emitted by the ultrasonic device is 1-2 MHz.

4. The controlled release ultrasonic rectal suppository according to claim 1, characterized in that: The ultrasonic frequency emitted by the ultrasonic device is 1.5 MHz.

5. The controlled release ultrasonic rectal suppository according to claim 1, characterized in that: The ultrasonic intensity emitted by the ultrasonic device is 0.5-3W / cm 2 .

6. The controlled release ultrasonic rectal suppository according to claim 1, characterized in that: The ultrasonic intensity emitted by the ultrasonic device is 1.5W / cm 2 .

7. The controlled release ultrasonic rectal suppository according to claim 1, characterized in that: The ultrasonic wave emitted by the ultrasonic device is a pulsed ultrasonic wave.

8. The controlled release ultrasonic rectal suppository according to claim 1, characterized in that: The control device is connected to the ultrasonic device and the power supply device in a wired or wireless manner, and the control device is in one of a human active control mode and an intelligent automatic control mode.

9. The controlled release ultrasonic rectal suppository according to claim 1, characterized in that: The power supply device is a disposable battery or a rechargeable battery, and the rechargeable battery is charged by wired power supply or wirelessly.

10. The controlled release ultrasonic rectal suppository according to claim 1, characterized in that: The ultrasonic rectal suppository is suitable for rapid absorption and administration of water-soluble macromolecular drugs to children with needle phobia, injection phobia, obesity or too young age.

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