A method for controlling drug administration time

Abstract

The present invention discloses a method for controlling drug administration time. The method for controlling drug administration time of the present invention comprises the following steps: S1: according to the drug administration time, drug administration amount and drug viscosity in a specific treatment scheme, the target permeability is calculated, that is, the product of the drug administration amount per unit time and the drug viscosity; S2: this step can be: Scheme 1: select a drug delivery device according to the target permeability, so that the deviation between the actual permeability of the drug delivery device and the target permeability is less than the allowable value; the actual permeability is the product of the volume of fluid exuded per unit time of the drug delivery device and the viscosity of the fluid; Scheme 2: determine the material, pore structure and pore distribution of the drug delivery device with a drug exudation area of ​​a microporous structure, adjust one or more of the porosity, pore size and number of pores of the drug delivery device, so that the deviation between the actual permeability of the drug delivery device and the target permeability is less than the allowable value; the actual permeability is the product of the volume of fluid exuded per unit time of the drug delivery device and the viscosity of the fluid.

Description

Technical Field

[0001] The present invention relates to a method for controlling drug administration time. Background Art

[0002] Drug-loaded medical devices have unique advantages as a combination of drugs and devices for treatment. Currently, drug-loaded medical devices on the market mainly pre-place drugs into specific polymer materials by coating, filling, blending or soaking, and rely on multiple factors such as drug penetration and diffusion in polymer materials and specific molecular forces between drugs and materials to control drug release time. The defects of this type of drug-loaded device are: first, this type of drug-loaded device has a narrow range of drug applications, and the drug-loaded device produced can only be used to control the release time of a certain specific drug, and its drug delivery time is fixed and difficult to adjust flexibly; second, the drug release of traditional drug-loaded devices involves the interaction between drug molecules and drug-loaded polymer materials, and the drug loading amount is limited. The design and development of drug release is very complicated, requiring a large number of experiments, a long cycle and high cost; finally, this type of drug-loaded device is pre-filled with drugs. Under the regulatory supervision of most countries, it needs to be declared in accordance with the approval process of drug-device combination, which is costly, complicated, time-consuming, and has a relatively low pass rate. At present, it is urgent to develop a method for controlling drug delivery time that can overcome the defects of the above-mentioned drug-loaded devices. Summary of the invention

[0003] The technical problem solved by the present invention is to overcome the defects of the drug-carrying device applicable to the drug-carrying device in the prior art in the control method of drug administration time, such as narrow drug application range, small drug loading amount, and difficult to flexibly adjust the drug administration time; long design and development cycle, high cost; complex approval process, long time, low pass rate, etc., and provide a method for controlling the drug administration time of the drug delivery device. The method of controlling drug administration time of the present invention can not only accurately control the drug administration time and the drug administration amount under the drug administration time, but also does not need to pre-infuse drugs in the applicable drug delivery device. Doctors and patients place fluid drugs in it according to the drug use recommendations when using it, and achieve the purpose of long-term stable drug administration through the control of the later device; since no specific drugs need to be placed in advance, this device can be declared according to the approval process of ordinary medical devices, with low cost, simple process, short time and high approval rate; at the same time, the method of controlling drug administration time of the present invention can flexibly adjust the drug administration time and drug administration amount according to different drugs, different diseases or specific treatment plans, and has a wider scope of application, especially for cavity-type drug administration routes. It has obvious application value; for patients who take long-term and multiple cavity drugs, it provides a more convenient drug administration method, reduces the frequency of drug administration, and improves the compliance of patients.

[0004] The present invention adopts the following technical solutions to solve the above technical problems:

[0005] The present invention provides a method for controlling drug administration time, the method comprising the following steps:

[0006] S1: According to the administration time, dosage, and drug viscosity in the specific treatment plan, the target permeability k is calculated, that is, the product of the dosage per unit time Q and the drug viscosity μ;

[0007] S2: This step can use either of the following two solutions:

[0008] Solution 1: Select a drug delivery device according to the target permeability, so that the deviation between the actual permeability of the drug delivery device and the target permeability is less than the allowable value; the actual permeability is the product of the volume Q' of the fluid permeated per unit time of the drug delivery device and the viscosity μ' of the fluid;

[0009] Option 2: Determine the material, pore structure and pore distribution of the drug delivery device with a drug exudation zone having a microporous structure, and adjust one or more of the porosity, pore size and number of pores of the drug delivery device so that the deviation between the actual permeability of the drug delivery device and the target permeability is less than the allowable value; the actual permeability is the product of the volume Q" of the fluid exuding from the drug delivery device per unit time and the viscosity μ" of the fluid.

[0010] In the present invention, the drug seeps out from the microporous structure of the drug seepage area of ​​the drug delivery device by gravity.

[0011] The drug delivery device in the present invention is generally suitable for a relatively long drug delivery time, and the drug delivery device is open to the outside world. It can be considered that the pressure inside the drug delivery device does not change significantly with time, so the seepage process can be considered as steady-state Darcy seepage. When the drug viscosity is determined, the permeability of the drug is only related to the pore structure characteristics of the drug delivery device, such as porosity, pore size, pore structure, pore distribution and material, and has nothing to do with the fluid itself.

[0012] The equation for steady-state Darcy flow is as follows:

[0013] k=QμL / ΔPA,

[0014] Where Q is the dosage per unit time, μm 3 / s; A is the area of ​​the drug leakage zone through which the fluid passes, μm 2 ; μ is the viscosity of the drug; ΔP is the pressure difference before and after passing through the drug exudation area, MPa; L is the length of the fluid passing through the drug exudation area, μm; k is the permeability, Dc or μm 2 .

[0015] For a specific drug delivery device, A, ΔP and L are all determined. The target permeability can be regarded as the product Qμ of the drug delivery volume per unit time Q and the drug viscosity μ, and the actual permeability of the drug delivery device can be regarded as the product of the unit exudate fluid volume and the fluid viscosity.

[0016] Those skilled in the art will understand that the dosage per unit time is the ratio of the dosage to the dosage time.

[0017] In S1, the medicine may be conventional in the art, and generally may include medicines for treatment and / or health care products for health care.

[0018] In solution 1 of S2, the shape of the applicator can be selected according to conventional practices in the art, and can generally be selected based on the shape of the administration site.

[0019] Preferably, when the drug administration site is the uterine cervix, the shape of the drug administration device is a Y-shaped structure, a ring structure or a T-shaped structure.

[0020] Preferably, when the administration site is the vagina or the rectum, the shape of the drug delivery device is a spherical structure, a bottle stopper structure or a rugby ball structure.

[0021] Preferably, when the administration site is subcutaneous muscle, the shape of the drug delivery device is a bottle stopper structure or a tube structure.

[0022] The spherical structure may generally include an inner ball, an outer ball sleeved outside the inner ball, and a spherical shell portion between the inner ball and the outer ball, wherein the shell of the spherical shell portion is the drug exudation area.

[0023] The bottle stopper type structure generally includes a conical drug reservoir and a microporous plug, wherein the plug is connected to the open end of the drug reservoir and the plug is the drug leakage area of ​​the drug delivery device.

[0024] Wherein, the annular structure includes an outer ring, an inner ring arranged inside the outer ring, and an annular wall between the outer ring and the inner ring, and the annular wall is the drug exudation area.

[0025] Wherein, the T-shaped structure comprises a drug administration tube and a fixing rod, one end of the drug administration tube is provided with the drug exudation area, and the fixing rod is vertically arranged at one end of the drug administration tube away from the drug exudation area.

[0026] Wherein, the tube-shaped structure comprises a drug administration tube, and one end of the drug administration tube is provided with the drug leakage area.

[0027] In Scheme 2 of S2, the microporous structure may be conventional in the art, preferably a highly interconnected microporous structure, such as an irregular microporous structure, a capillary microporous structure or a fiber stacked microporous structure, more preferably a capillary microporous structure.

[0028] The highly interconnected microporous structure can control the seepage rate of the liquid, thereby achieving the purpose of making the liquid stay in the applicator for a longer time, that is, achieving a sustained release effect.

[0029] The irregular microporous structure can be prepared by a polymer foaming method.

[0030] The polymer may be conventional in the art, preferably one or more of PU, TPE and EVA.

[0031] The capillary microporous structure may be conventional in the art, and generally, a plurality of micropores may be arranged in parallel.

[0032] The fiber stacking type microporous structure may be conventional in the art, and may generally be formed by stacking fibers layer by layer. The fibers may be obtained by conventional methods in the art, preferably by hot melt extrusion of polymer materials.

[0033] In Scheme 2 of S2, the material may be conventional in the art, preferably one or more of polyurethane, PU, ​​EVA, TPU, TPES, PP, PE, ABS and PLA.

[0034] The polyurethane is preferably medical polyurethane, such as Tecoflex EG80A.

[0035] In Scheme 2 of S2, the pore structure may be conventional in the art, preferably a highly interconnected microporous structure, such as an irregular microporous structure, a capillary microporous structure or a fiber stacked microporous structure, more preferably a capillary microporous structure.

[0036] The highly interconnected microporous structure can control the seepage rate of the liquid, thereby achieving the purpose of making the liquid stay in the applicator for a longer time, that is, achieving a sustained release effect.

[0037] The irregular microporous structure can be prepared by a polymer foaming method.

[0038] The polymer may be conventional in the art, preferably one or more of PU, TPE and EVA.

[0039] The capillary microporous structure may be conventional in the art, and generally, a plurality of micropores may be arranged in parallel.

[0040] The fiber stacking type microporous structure may be conventional in the art, and may generally be formed by stacking fibers layer by layer. The fibers may be obtained by conventional methods in the art, preferably by hot melt extrusion of polymer materials.

[0041] In the second scheme of S2, the hole distribution method can be conventional in the art, generally can be uniform distribution or uneven distribution, preferably uniform distribution.

[0042] In certain preferred embodiments of Scheme 2 of S2, when the pore structure is the irregular microporous structure, the porosity of the applicator is adjusted so that the deviation between the actual permeability of the applicator and the target permeability is less than an allowable value.

[0043] Among them, the method for adjusting the porosity of the applicator with irregular microporous structure can be conventional in the art, generally achieved by changing one or more of the raw material ratio, reaction temperature, ventilation volume, additive type, additive ratio and crosslinking reaction time during the foaming process.

[0044] In certain preferred embodiments of Scheme 2 of S2, when the pore structure is the capillary-type microporous structure, the porosity, pore size or number of holes of the applicator is adjusted so that the deviation between the actual permeability of the applicator and the target permeability is less than an allowable value.

[0045] The porosity of the applicator with a capillary microporous structure can be adjusted by a conventional method in the art, preferably by adjusting the pore size and / or the number of pores.

[0046] In certain preferred embodiments of Scheme 2 of S2, when the pore structure is the fiber stacking type microporous structure, the porosity of the applicator is adjusted so that the deviation between the actual permeability of the applicator and the target permeability is less than an allowable value.

[0047] The porosity of the drug delivery device with a fiber stacking type microporous structure can be adjusted by a conventional method in the art, preferably by changing the number of fiber stacking layers.

[0048] In the second scheme of S2, the porosity can be adjusted within the conventional range in the art, preferably within the range of 30 to 80%.

[0049] In the second scheme of S2, the adjustment range of the aperture can be conventional in the art, preferably 0.5 mm to 1.5 mm.

[0050] In a preferred embodiment of Scheme 2 of S2, the pore structure of the applicator is determined to be a capillary-type microporous structure, the pore distribution is uniformly distributed, and the material is medical polyurethane. The number of holes in the applicator is adjusted so that the deviation between the actual permeability of the applicator and the target permeability is less than the allowable value.

[0051] In a preferred embodiment of Scheme 2 of S2, the pore structure of the applicator is determined to be a capillary-type microporous structure, the pore distribution is uniformly distributed, and the material is medical polyurethane. The pore size and the number of holes are adjusted, and the pore size is adjusted between 0.5 mm and 1.5 mm, so that the deviation between the actual permeability of the applicator and the target permeability is less than the allowable value.

[0052] In S2, the test method of the actual permeability can be conventional in the art, generally using a test fluid to test the seepage volume per unit time, and the product of the seepage volume per unit time and the viscosity of the test fluid is the actual permeability.

[0053] The test fluid may be conventional in the art, preferably water.

[0054] Among common drug fluids, water has the lowest viscosity and can easily penetrate out of the drug dispenser. If the designed drug dispenser can keep water for a longer period of time, the time it takes for drug fluids with higher viscosity to completely penetrate out of the drug dispenser, that is, the drug delivery time, will be longer, making it easier to achieve the purpose of controlling the slow release of the drug.

[0055] In S2, the allowable value may be conventional in the art, and may generally be 0.5 to 20%.

[0056] In S2, when the drug is a hormone drug, the allowable value is preferably 0.5 to 3, for example 2%.

[0057] In S2, when the drug is a traditional Chinese medicine, the allowable value is preferably 10-20%.

[0058] Based on the common knowledge in this field, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0059] The reagents and raw materials used in the present invention are commercially available.

[0060] The positive and progressive effects of the present invention are:

[0061] (1) The method of the present invention can accurately control the administration time and speed;

[0062] (2) In the method for controlling drug administration time of the present invention, the drug delivery device does not need to be pre-filled with drugs, and can be applied for according to the approval process of medical devices, which has low cost, simple process, short time and high approval rate;

[0063] (3) In the method of the present invention, the drug delivery device can be used for different drugs, and the drug delivery time can be flexibly adjusted according to different diseases or specific treatment plans, so that the application range is wider and the therapeutic effect of the drug is better.

[0064] (4) For patients who need long-term and multiple intracavitary drug administration, it provides a more convenient drug administration method, reduces the frequency of drug administration, and improves patient compliance. BRIEF DESCRIPTION OF THE DRAWINGS

[0065] Figure 1 It is a schematic diagram of a spherical structure drug delivery device;

[0066] Figure 2 This is a schematic diagram of a rugby-shaped drug delivery device;

[0067] Figure 3 It is a schematic diagram of a ring-shaped drug delivery device;

[0068] Figure 4 This is a schematic diagram of a bottle stopper-shaped structure drug delivery device;

[0069] Figure 5 It is a schematic diagram of a T-shaped structure drug delivery device;

[0070] Figure 6 It is a schematic diagram of a tube-shaped structure drug delivery device;

[0071] Figure 7 Schematic diagram of irregular microporous structure;

[0072] Figure 8 Schematic diagram of capillary microporous structure;

[0073] Fig. 9 Schematic diagram of fiber stacking microporous structure.

[0074] Reference numerals:

[0075] 1-drug exudation area; 2-drug storage area; 3-drug adding channel; 4-fixing rod. DETAILED DESCRIPTION

[0076] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0077] Example 1

[0078] This embodiment is a specific implementation of the second solution of the present invention, and includes the following steps:

[0079] S1: Calculate target permeability

[0080] Assume that the drug is water, the viscosity μ is 1 cp, the administration time is set to 4 hours, the dosage is 5 mL, and the target permeability k = Q×μ.

[0081] The target permeability is calculated as follows:

[0082] S2: Design of drug delivery device

[0083] The medication site is the uterine cervix, and the shape of the medication applicator is determined Figure 1 The spherical structure Figure 3 The ring structure or Figure 5 When the administration site is vaginal or rectal, the shape of the applicator can also be determined as Figure 2 The rugby-type structure shown or Figure 4 The bottle stopper structure shown in the figure; when the administration site is the subcutaneous muscle, the shape of the applicator can also be determined as Figure 6 The microporous structure of the fixed drug leakage zone 1 is as follows Figure 8 The capillary microporous structure shown in Fig. 9 The fiber stacking type microporous structure shown or Figure 7 The irregular pore structure shown has a uniform pore distribution and the material is Lubrizol's medical polyurethane Tecoflex EG80A.

[0084] The pore structure is Figure 8 In the capillary microporous structure shown, the pore size is fixed at 0.5 mm, and the porosity is changed by changing the number of holes so that the deviation between the actual permeability and the target permeability is within 10%, that is, the total permeation time of 5 mL of water in the obtained dispenser is 3.6 to 4.4 hours.

[0085] The pore structure is Fig. 9 In the fiber stacking microporous structure shown, the porosity is changed by changing the number of fiber stacking layers so that the deviation between the actual permeability and the target permeability is within 10%, that is, the total permeation time of 5 mL of water in the obtained applicator is 3.6 to 4.4 hours.

[0086] The pore structure is Figure 7 When the irregular microporous structure is shown, the porosity is changed by adjusting the raw material ratio, reaction temperature, ventilation volume, additive type, additive ratio or cross-linking reaction time during the foaming process so that the deviation between the actual permeability and the target permeability is within 10%, that is, the total seepage time of 5 mL of water in the obtained dispenser is 3.6 to 4.4 h.

[0087] Example 2

[0088] This embodiment is a specific implementation of the second solution of the present invention, and includes the following steps:

[0089] S1: Calculate target permeability

[0090] The pre-administered drug is a gynecological antibacterial gel with a viscosity μ of 30,000 cp, a set administration time of 4 hours, a dosage of 5 mL, and a target permeability k = Q × μ.

[0091] S2: Design of drug delivery device

[0092] The administration site is vaginal, and the shape of the applicator is determined as follows Figure 4 The bottle stopper structure shown in FIG. 1 has a microporous structure in the drug exudation area 1 as shown in FIG. Figure 8 The capillary microporous structure shown in the figure has a uniform pore distribution and is made of Lubrizol's medical polyurethane Tecoflex EG80A. The porosity is fixed at 40%, and the pore size and number of pores are adjusted so that the deviation between the actual permeability and the target permeability is within 20%, even if 5 mL of S1 vaginal gel is completely exuded in the designed bottle plug type applicator in 3.2 to 4.8 hours. The pore size of the applicator was finally determined to be 1.5 mm.

[0093] Example 3

[0094] This embodiment is a specific implementation of the first solution of the present invention, and includes the following steps:

[0095] S1: Calculate target permeability

[0096] S1 is the same as S1 of Example 1.

[0097] S2: Select the applicator

[0098] The administration site is the vagina, and the shape of the applicator is determined to be a bottle stopper type structure. Actual permeability tests are carried out on a large number of applicators with different pore structures, materials, porosities, pore sizes and numbers of holes. The deviation between the actual permeability and the target permeability is made within 10%. The test fluid is water, and it takes 3.6 to 4.4 hours for 5 mL of water to completely seep out of the applicator.

[0099] Example 4

[0100] The specific use process of the drug delivery device designed or selected in Examples 1 to 3 is as follows: the drug or health product can be loaded into the drug storage area 2 through the drug adding channel 3, and the drug or health product in the drug storage area 2 seeps out to the drug delivery site, such as the rectum, vagina or uterine cervix, through the microporous structure of the drug seepage area 1. The T-shaped drug delivery device also includes a fixing rod 4, which can be fixed at the uterine cervical opening.

Claims

1. A method for determining the administration time, characterized in that: The method comprises the following steps: S1: According to the administration time, dosage, and drug viscosity in the specific treatment plan, the target permeability k is calculated, that is, the product of the dosage per unit time Q and the drug viscosity μ; S2: Determine the material, pore structure and pore distribution of the drug delivery device with a drug exudation area having a microporous structure, and adjust one or more of the porosity, pore size and number of pores of the drug delivery device so that the deviation between the actual permeability of the drug delivery device and the target permeability is less than the allowable value; the actual permeability is the product of the volume Q" of the fluid exuded per unit time of the drug delivery device and the viscosity μ" of the fluid; The microporous structure is a highly interconnected microporous structure; The porosity is adjusted in the range of 30 to 80%; The adjustment range of the aperture is 0.5 mm to 1.5 mm.

2. The method for determining the administration time according to claim 1, wherein: The shape of the applicator is a spherical structure, an annular structure or a T-shaped structure; or, the shape of the applicator is a spherical structure, a bottle stopper structure or a rugby ball structure; or, the shape of the applicator is a bottle stopper structure or a tube structure.

3. The method for determining the administration time according to claim 1, characterized in that: The microporous structure is an irregular microporous structure, a capillary microporous structure or a fiber stacking microporous structure.

4. The method for determining the administration time according to claim 3, characterized in that: The irregular microporous structure is made by foaming a polymer; And / or, the capillary type microporous structure is a plurality of micropores arranged in parallel; And / or, the fiber stacking type microporous structure is formed by stacking fibers layer by layer.

5. The method for determining the administration time according to claim 4, characterized in that: The polymer is one or more of PU, TPE and EVA; And / or, the fibers are obtained by hot melt extrusion of polymer materials.

6. The method for determining the administration time according to claim 1, wherein: The material is one or more of polyurethane, PU, ​​EVA, TPU, TPES, PP, PE, ABS and PLA; And / or, the holes are distributed in a uniform or non-uniform manner.

7. The method for determining the administration time according to claim 6, characterized in that: The polyurethane is medical polyurethane.

8. The method for determining the administration time according to claim 6, characterized in that: The polyurethane is TecoflexEG80A.

9. The method for determining the administration time according to claim 3, characterized in that: When the pore structure is the irregular microporous structure, the porosity of the applicator is adjusted so that the deviation between the actual permeability of the applicator and the target permeability is less than the allowable value.

10. The method for determining the administration time according to claim 9, characterized in that: The porosity of the applicator with irregular microporous structure is adjusted by changing one or more of the raw material ratio, reaction temperature, ventilation volume, additive type, additive ratio and cross-linking reaction time during the foaming process.

11. The method for determining the administration time according to claim 3, characterized in that: When the pore structure is the capillary microporous structure, the porosity, pore size or number of pores of the applicator is adjusted so that the deviation between the actual permeability of the applicator and the target permeability is less than the allowable value.

12. The method for determining the administration time according to claim 11, characterized in that: The porosity of the capillary microporous structured applicator is adjusted by adjusting the pore size and / or the number of pores.

13. The method for determining the administration time according to claim 3, characterized in that: When the pore structure is the fiber stacking type microporous structure, the porosity of the applicator is adjusted so that the deviation between the actual permeability of the applicator and the target permeability is less than the allowable value.

14. The method for determining the administration time according to claim 13, characterized in that: The porosity of the drug delivery device with a fiber stacking type microporous structure is adjusted by changing the number of fiber stacking layers.

15. The method for determining the administration time according to claim 1, characterized in that: Determine that the pore structure of the drug delivery device is a capillary microporous structure, the pore distribution is uniformly distributed, and the material is medical polyurethane, and adjust the number of holes of the drug delivery device so that the deviation between the actual permeability of the drug delivery device and the target permeability is less than the allowable value; Alternatively, the pore structure of the applicator is determined to be a capillary microporous structure, the pore distribution is uniformly distributed, and the material is medical polyurethane, and the pore size and the number of pores are adjusted, and the pore size is adjusted between 0.5 mm and 1.5 mm, so that the deviation between the actual permeability of the applicator and the target permeability is less than the allowable value; Alternatively, the pore structure of the applicator is determined to be a fiber stacking type microporous structure, the pore distribution is uniformly distributed, and the material is medical polyurethane, and the porosity is changed by changing the number of fiber stacking layers so that the deviation between the actual permeability of the applicator and the target permeability is less than the allowable value; Alternatively, the pore structure of the applicator is determined to be an irregular microporous structure, the pore distribution is uniformly distributed, and the material is medical polyurethane. The porosity is changed by adjusting the raw material ratio, reaction temperature, ventilation volume, additive type, additive ratio or cross-linking reaction time during the foaming process so that the deviation between the actual permeability of the applicator and the target permeability is less than the allowable value.

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