CN112999144B - Ionic electroosmosis transdermal drug delivery system - Google Patents
Ionic electroosmosis transdermal drug delivery system Download PDFInfo
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/20—Applying electric currents by contact electrodes continuous direct currents
- A61N1/30—Apparatus for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body, or cataphoresis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
- A61N1/325—Applying electric currents by contact electrodes alternating or intermittent currents for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Abstract
The invention discloses an iontophoresis transdermal drug delivery system, and relates to the technical field of biological medicines. The system is composed of an ion introduction instrument, a positive electrode plate, a negative electrode plate, positive electrode drug storage gel and negative electrode electrolyte storage gel, wherein the ion introduction instrument is respectively connected with the positive electrode plate and the negative electrode plate through leads, the positive electrode drug storage gel is arranged on the positive electrode plate, and the negative electrode electrolyte storage gel is arranged on the negative electrode plate. Compared with a control transdermal drug delivery system without iontophoresis, the iontophoresis transdermal drug delivery system of the present invention significantly promotes transdermal absorption of drugs, and exhibits a significant and good blood pressure lowering effect and a benign prostatic hypertrophy inhibitory effect. The transdermal rate of the drug is proportional to the current intensity, the drug concentration, and inversely proportional to the reservoir gel pH and the concentration of the competitive salt NaCl.
Description
Technical Field
The invention relates to the technical field of biological medicines, in particular to an iontophoresis transdermal drug delivery system.
Background
Terazosin hydrochloride (TEH) is an anti-adrenergic agent, is selective alpha 1 Receptor inhibitors, which can be administered for a long period of time, are mainly used for the treatment of essential hypertension and benign prostatic hyperplasia. The action mechanism is to block the alpha of vascular smooth muscle cells 1 The receptor inhibits the contraction action of catecholamine on vascular smooth muscle, expands peripheral blood vessels and reduces blood flow resistance, thereby generating the effect of reducing blood pressure; relax smooth muscle of prostate and bladder, thereby relieving symptoms such as dysuria caused by prostatic hyperplasia.
Hypertension is one of three chronic diseases in the world, the hypertension is mainly harmful to the induction of cardiovascular and cerebrovascular diseases, stroke, myocardial infarction, heart failure and chronic kidney diseases are main complications of the hypertension, and the hypertension is mainly controlled clinically through oral antihypertensive drugs. Benign prostatic hyperplasia is also called prostatic hypertrophy and prostatic adenomatous hyperplasia, has the main symptoms of frequent micturition, urgent micturition, progressive dysuria and the like, is a common disease affecting the quality of life and the health condition of middle-aged and old men, has higher risk in surgical treatment, has sequelae such as urinary incontinence, sexual dysfunction and the like, and aims to improve the quality of life of patients and reduce the adverse reaction of medicaments as much as possible in the medicament treatment.
Transdermal administration is an administration route through skin administration, and compared with the conventional oral administration preparation, the transdermal administration preparation can avoid the first pass effect of liver and intestine in the drug absorption process, effectively reduce the side effect of gastrointestinal tract, maintain constant blood concentration in a treatment window, avoid the peak valley phenomenon caused by oral drug absorption, and reduce the toxic and side effect of the drug; the administration is convenient, and the patient compliance is high. The terazosin hydrochloride is developed into a transdermal drug delivery preparation, the drug can maintain a stable and effective blood concentration in vivo, and adverse reactions such as orthostatic hypotension, headache, dizziness and the like caused by oral administration can be reduced; also has the advantages of long-acting effect, convenient use, good patient compliance and the like, and is particularly suitable for middle-aged and elderly patients with hypertension and benign prostatic hyperplasia.
However, the skin is a natural barrier of the human body, and most drugs cannot be directly absorbed transdermally to achieve therapeutic blood levels. Terazosin hydrochloride is an ionic drug and is difficult to permeate the stratum corneum of a skin lipid bilayer, and the alkalized terazosin molecules are unstable and easy to degrade. Thus, terazosin hydrochloride cannot be administered transdermally to therapeutic concentrations by means of chemical facilitators.
Iontophoresis is a process of transferring ions or neutral molecules actively across biological barriers driven by an external electric field, and is now widely used in transdermal drug delivery. The system consists of a power supply, electrodes, a control circuit, a drug reservoir, an electrolyte reservoir and the like. Iontophoresis shortens the time spent in the process of enriching the medicine in the skin and transferring layer by layer through the action of electroosmotic flow, electric field force and the like on the basis of original passive transfer, so that the medicine can quickly enter the blood circulation of a human body to generate the medicine effect, and is particularly suitable for delivering ionic and small molecular peptide medicines which are not suitable for permeating skin lipid bilayers.
Compared with the conventional oral preparation, the transdermal drug delivery preparation has many advantages, but the ionic drug terazosin hydrochloride has poor transdermal penetration capability, and cannot be prepared into the conventional transdermal drug delivery preparation.
Disclosure of Invention
In view of the problems in the prior art, the present invention provides an iontophoresis transdermal drug delivery system. The electro-osmosis transdermal drug delivery system combines terazosin hydrochloride with ion electro-osmosis equipment to complete the transdermal drug delivery process, has good transdermal permeation effect, obvious blood pressure lowering effect, and in vivo blood concentration obviously higher than that of non-ion electro-osmosis gel, and can be developed into a TEH electro-osmosis transdermal drug delivery system for treating hypertension and benign prostatic hyperplasia.
In order to achieve the purpose, the invention adopts the following technical scheme: an iontophoresis transdermal drug delivery system is composed of an iontophoresis instrument, a positive electrode plate, a negative electrode plate, a positive electrode drug storage gel and a negative electrode electrolyte storage gel, wherein the iontophoresis instrument is connected with the positive electrode plate and the negative electrode plate respectively through conducting wires, the positive electrode drug storage gel is arranged on the positive electrode plate, and the negative electrode electrolyte storage gel is arranged on the negative electrode plate;
the positive electrode drug storage gel is prepared by the following method: weighing 0.1-7% of main drug, 1.5-10% of excipient, 1-25% of humectant, 0.01-1% of pH regulator, 0.01-1% of preservative and 63-98% of first solvent according to the weight ratio; dissolving a humectant and a preservative in 56-97% of the first solvent by weight, uniformly mixing, then adding an excipient for uniform dispersion to obtain a mixed solution, dissolving the main drug in the remaining amount of the first solvent, mixing the dissolved main drug with the mixed solution, swelling overnight, adjusting the pH to 4-10 by using a pH regulator, and finally centrifuging for 5-30 min at 2000-10000 rmp to remove air bubbles to obtain the anode drug storage gel.
The negative electrode electrolyte reservoir gel is prepared by the following method: weighing 0.8-10% of excipient, 5-20% of humectant, 0.01-0.8% of preservative, 0.03-0.9% of pH regulator and 69-95% of second solvent according to the weight ratio, dissolving the humectant and the preservative in the second solvent, uniformly mixing, then adding the excipient, uniformly dispersing, regulating the pH to 4-8 by using the pH regulator, centrifuging for 5-30 min at 2000-10000 rmp to remove bubbles, and obtaining the cathode electrolyte storage gel.
Further, the main drug is terazosin hydrochloride or other medically acceptable salts of terazosin.
Further, the first solvent is ultrapure water.
Further, the current density used by the ion introduction instrument is 0.1 to 0.4mA cm -2 。
Further, the excipient is formed by mixing one or two of polyvinyl pyrrolidone, hydroxypropyl cellulose, carbomer and polyvinyl alcohol according to any proportion.
Further, the humectant is formed by mixing one or two of 1, 2-propylene glycol and glycerol according to any proportion.
Further, the pH regulator is one or two of triethanolamine and triethylamine which are mixed according to any proportion.
Furthermore, the preservative is prepared by mixing one or more of ethylparaben, benzoic acid and salts thereof, sorbic acid and salts thereof, dehydroacetic acid and sodium salts, and parabens according to any proportion.
Further, the second solvent is formed by mixing one or more of phosphate buffer solution, acetic acid buffer solution, citric acid buffer solution and boric acid buffer solution according to any proportion.
Compared with the prior art, the invention has the following beneficial effects: the terazosin hydrochloride is available in the dosage forms of tablets and capsules, but the incidence rate of adverse reactions of the terazosin hydrochloride is more than 10%, and the terazosin hydrochloride is often accompanied by side effects of mild to moderate degrees, even severe dizziness, weakness, orthostatic hypotension and the like, and is mainly related to administration dosage fluctuation. The terazosin hydrochloride ion electro-osmosis transdermal drug delivery system has the characteristic of stable blood concentration through transdermal drug delivery, has the advantage of regulating and controlling the drug release rate, and has the following advantages compared with an oral administration way: 1) Due to the speed limiting effect and the storage effect of the skin, the peak reaching time of the blood concentration is delayed, the elimination half-life period is prolonged, and the relatively stable state is easier to maintain; 2) The administration process of the drug can be stopped conveniently and timely when serious badness is generated by a patient, and the safety of the drug administration is improved; 3) The dosage of the terazosin hydrochloride iontophoresis transdermal drug delivery system can be controlled by adjusting the current intensity, the acting time and the frequency of the terazosin hydrochloride iontophoresis transdermal drug delivery system. The terazosin hydrochloride iontophoretic transdermal drug delivery system of the present invention can be effectively used for the physiotherapy of hypertension and benign prostatic hyperplasia. The ion electro-osmosis drug delivery product which can be portable can be developed by combining a flexible wearable electro-osmosis drug delivery system product in a long term.
Drawings
FIG. 1 is a flow chart of a process for preparing a positive drug depot gel;
FIG. 2 is a graph of the skin cumulative drug permeation versus time for the isolated guinea pigs of examples 1-3 iontophoretic systems;
FIG. 3 is a graph of plasma concentration versus time for rats in an iontophoresis system of the present invention;
FIG. 4 is a graph of blood pressure versus time for rats in the model of hypertension in iontophoresis system according to example 1;
FIG. 5 is a graph of cumulative permeation of a drug versus time for different current levels;
FIG. 6 is a graph of steady-state transdermal permeation rate versus current intensity for a drug;
FIG. 7 is a graph of the relationship between steady-state transdermal permeation rate of the drug and the concentration of terazosin hydrochloride;
FIG. 8 is a graph of steady-state transdermal permeation rate versus pH of a drug;
FIG. 9 is a graph of steady-state transdermal permeation rate of a drug versus NaCl concentration.
Detailed Description
The following examples are given to further illustrate the present invention, but the examples are only for illustration of the present invention and not to limit the present invention, therefore, any simple modification of the present invention under the premise of the method of the present invention is within the scope of the present invention claimed.
Example 1
The invention provides a preparation method of a positive drug storage gel, as shown in figure 1, the specific process is as follows: weighing 0.2% of terazosin hydrochloride, 3% of polyvinylpyrrolidone, 9% of glycerol, 6% of 1, 2-propylene glycol, 0.08% of triethanolamine, 0.12% of ethylparaben and 81.6% of ultrapure water according to the weight ratio; dissolving glycerol, 1, 2-propylene glycol and ethylparaben in 90% of ultrapure water by weight, uniformly mixing, then adding polyethylene pyrrolidone for uniform dispersion to obtain a mixed solution, dissolving terazosin hydrochloride in the rest ultrapure water, mixing the dissolved terazosin hydrochloride with the mixed solution, swelling overnight, adjusting the pH to 5.2 with triethanolamine, and finally centrifuging for 30min at 2000rmp to remove bubbles to obtain the anode drug storage gel.
The invention provides a preparation method of a cathode electrolyte storage gel, which comprises the following specific steps: weighing 3.5% of polyvinylpyrrolidone, 10% of glycerol, 0.12% of ethylparaben, 0.08% of triethanolamine and 86.3% of citric acid buffer solution according to the weight ratio, dissolving the glycerol and the ethylparaben in the citric acid buffer solution, uniformly mixing, adding the polyvinylpyrrolidone into the mixture, uniformly dispersing, adjusting the pH value to 5.2 by the triethanolamine, and centrifuging the mixture for 30min at 2000rmp to remove bubbles to obtain the cathode electrolyte reservoir gel.
The prepared positive electrode drug storage gel, negative electrode electrolyte storage gel, an iontophoresis apparatus, a positive electrode plate and a negative electrode plate jointly form an iontophoresis transdermal drug delivery system, the iontophoresis apparatus is respectively connected with the positive electrode plate and the negative electrode plate through leads, the positive electrode drug storage gel is arranged on the positive electrode plate, and the negative electrode electrolyte storage gel is arranged on the negative electrode plate.
Example 2
The invention provides a preparation method of an anode drug storage gel, which comprises the following specific steps: weighing 0.1% of terazosin hydrochloride, 2.0% of hydroxypropyl cellulose, 1% of glycerol, 0.01% of triethylamine, 0.01% of paraben and 96.88% of ultrapure water according to the weight ratio; dissolving glycerol and paraben in 97% of ultrapure water by weight, uniformly mixing, then adding hydroxypropyl cellulose for uniform dispersion to obtain a mixed solution, dissolving terazosin hydrochloride in the rest ultrapure water, mixing the dissolved terazosin hydrochloride with the mixed solution, swelling overnight, adjusting the pH to 4 with triethylamine, and finally centrifuging for 15min at 5000rmp to remove bubbles to obtain the anode drug storage gel.
The invention provides a preparation method of a cathode electrolyte storage gel, which comprises the following specific steps: weighing 0.8% of polyvinylpyrrolidone, 5% of glycerol, 0.01% of nipagin ester, 0.03% of triethylamine and 94.16% of 20mM sodium dihydrogen phosphate solution according to the weight ratio, dissolving the glycerol and the nipagin ester in the 20mM sodium dihydrogen phosphate solution, uniformly mixing, then adding the polyvinylpyrrolidone for uniform dispersion, adjusting the pH value to 4.5 by using the triethylamine, and centrifuging for 15min at 5000rmp to remove bubbles to obtain the cathode electrolyte storage gel.
The prepared positive electrode drug storage gel, negative electrode electrolyte storage gel, an iontophoresis apparatus, a positive electrode plate and a negative electrode plate jointly form an iontophoresis transdermal drug delivery system, the iontophoresis apparatus is respectively connected with the positive electrode plate and the negative electrode plate through leads, the positive electrode drug storage gel is arranged on the positive electrode plate, and the negative electrode electrolyte storage gel is arranged on the negative electrode plate.
Example 3
The invention provides a preparation method of an anode drug storage gel, which comprises the following specific steps: weighing 0.3% of terazosin hydrochloride, 7.5% of polyvinyl alcohol, 2.5% of hydroxypropyl cellulose, 25% of 1, 2-propylene glycol, 1% of sorbic acid, 0.1% of triethanolamine and 63.6% of ultrapure water according to the weight ratio; dissolving 1, 2-propylene glycol and sorbic acid in 88% of ultrapure water by weight, uniformly mixing, then adding hydroxypropyl cellulose and polyvinyl alcohol for uniform dispersion to obtain a mixed solution, dissolving terazosin hydrochloride in the rest ultrapure water, mixing the dissolved terazosin hydrochloride with the mixed solution, swelling overnight, adjusting the pH to 6.7 with triethanolamine, and finally centrifuging for 5min at 10000rmp to remove bubbles to obtain the anode drug storage gel.
The invention provides a preparation method of a cathode electrolyte storage gel, which comprises the following specific steps: weighing 6% of polyvinyl alcohol, 2% of hydroxypropyl cellulose, 20% of 1, 2-propylene glycol, 0.8% of sorbic acid, 0.35% of triethanolamine and 70.85% of 20mM sodium dihydrogen phosphate solution according to the weight ratio, dissolving the 1, 2-propylene glycol and the sorbic acid in the 20mM sodium dihydrogen phosphate solution, uniformly mixing, then adding the hydroxypropyl cellulose and the polyvinyl alcohol for uniform dispersion, adjusting the pH to 7 by the triethanolamine, and centrifuging for 5min at 10000rmp to remove bubbles to obtain the cathode electrolyte reservoir gel.
The prepared positive electrode drug storage gel, negative electrode electrolyte storage gel, an iontophoresis apparatus, a positive electrode plate and a negative electrode plate jointly form an iontophoresis transdermal drug delivery system, the iontophoresis apparatus is respectively connected with the positive electrode plate and the negative electrode plate through leads, the positive electrode drug storage gel is arranged on the positive electrode plate, and the negative electrode electrolyte storage gel is arranged on the negative electrode plate.
Example 4
The invention provides a preparation method of an anode drug storage gel, which comprises the following specific steps: weighing 0.5% of terazosin hydrochloride, 3% of hydroxypropyl cellulose, 15% of 1, 2-propylene glycol, 0.1% of nipagin ester, 0.05% of triethanolamine and 81.35% of ultrapure water according to the weight ratio; dissolving 1, 2-propylene glycol and nipagin ester in 86% of ultrapure water by weight, uniformly mixing, then adding hydroxypropyl cellulose for uniform dispersion to obtain a mixed solution, dissolving terazosin hydrochloride in the rest ultrapure water, mixing the dissolved terazosin hydrochloride with the mixed solution, swelling overnight, adjusting the pH to 5 by triethanolamine, and finally centrifuging for 5min at 10000rmp to remove bubbles to obtain the anode drug storage gel.
The invention provides a preparation method of a cathode electrolyte storage gel, which comprises the following specific steps: weighing 3% of hydroxypropyl cellulose, 15% of 1, 2-propylene glycol, 0.1% of nipagin ester, 0.04% of triethanolamine and 81.86% of boric acid buffer solution according to the weight ratio, dissolving the 1, 2-propylene glycol and the nipagin ester in the boric acid buffer solution, uniformly mixing, adding the hydroxypropyl cellulose for uniform dispersion, adjusting the pH value to 5 by the triethanolamine, centrifuging for 5min at 10000rmp to remove air bubbles, and obtaining the cathode electrolyte reservoir gel.
The prepared positive electrode drug storage gel, negative electrode electrolyte storage gel, an iontophoresis apparatus, a positive electrode plate and a negative electrode plate jointly form an iontophoresis transdermal drug delivery system, the iontophoresis apparatus is respectively connected with the positive electrode plate and the negative electrode plate through leads, the positive electrode drug storage gel is arranged on the positive electrode plate, and the negative electrode electrolyte storage gel is arranged on the negative electrode plate.
Example 5
The invention provides a preparation method of an anode drug storage gel, which comprises the following specific steps: weighing 0.5% of terazosin hydrochloride, 8% of polyvinylpyrrolidone, 15% of 1, 2-propylene glycol, 0.15% of dehydroacetic acid, 1.0% of triethanolamine and 75.35% of ultrapure water according to the weight ratio; dissolving 1, 2-propylene glycol and dehydroacetic acid in 86% of ultrapure water by weight, uniformly mixing, then adding polyvinylpyrrolidone for uniform dispersion to obtain a mixed solution, dissolving terazosin hydrochloride in the rest ultrapure water, mixing the dissolved terazosin hydrochloride with the mixed solution, swelling overnight, adjusting the pH to 10 by triethanolamine, and finally centrifuging for 5min at 10000rmp to remove bubbles to obtain the anode drug storage gel.
The invention provides a preparation method of a cathode electrolyte storage gel, which comprises the following specific steps: weighing 10% of polyvinylpyrrolidone, 20% of 1, 2-propylene glycol, 0.1% of dehydroacetic acid, 0.9% of triethanolamine and 69% of 50mM sodium hydrogen phosphate aqueous solution according to the weight ratio, dissolving the 1, 2-propylene glycol and the dehydroacetic acid in the 50mM sodium hydrogen phosphate aqueous solution, uniformly mixing, then adding the polyvinylpyrrolidone for uniform dispersion, adjusting the pH value to 8 by using the triethanolamine, centrifuging for 5min at 10000rmp to remove bubbles, and obtaining the cathode electrolyte reservoir gel.
The prepared positive electrode drug storage gel, negative electrode electrolyte storage gel, an iontophoresis apparatus, a positive electrode plate and a negative electrode plate jointly form an iontophoresis transdermal drug delivery system, the iontophoresis apparatus is respectively connected with the positive electrode plate and the negative electrode plate through leads, the positive electrode drug storage gel is arranged on the positive electrode plate, and the negative electrode electrolyte storage gel is arranged on the negative electrode plate.
Example 6
The invention provides a preparation method of an anode drug storage gel, which comprises the following specific steps: weighing 7% of terazosin hydrochloride, 1.5% of carbomer, 15% of 1, 2-propylene glycol, 0.1% of sodium benzoate, 0.35% of triethanolamine and 76.05% of ultrapure water according to the weight ratio; dissolving 1, 2-propylene glycol and sodium benzoate in 56% of ultrapure water by weight, uniformly mixing, then adding carbomer for uniform dispersion to obtain a mixed solution, dissolving terazosin hydrochloride in the rest ultrapure water, mixing the dissolved terazosin hydrochloride with the mixed solution, swelling overnight, adjusting the pH to 10 by triethanolamine, and finally centrifuging for 5min at 10000rmp to remove air bubbles to obtain the anode drug storage gel.
The invention provides a preparation method of a cathode electrolyte storage gel, which comprises the following specific processes: weighing 1.5% of carbomer, 15% of 1, 2-propylene glycol, 0.1% of sodium benzoate, 0.25% of triethanolamine and 83.15% of sodium acetate buffer solution according to the weight ratio, dissolving the 1, 2-propylene glycol and the sodium benzoate in the sodium acetate buffer solution, uniformly mixing, adding the carbomer for uniform dispersion, adjusting the pH value to 5 by using the triethanolamine, centrifuging for 5min at 10000rmp to remove air bubbles, and obtaining the cathode electrolyte reservoir gel.
The prepared positive electrode drug storage gel, negative electrode electrolyte storage gel, an iontophoresis apparatus, a positive electrode plate and a negative electrode plate jointly form an iontophoresis transdermal drug delivery system, the iontophoresis apparatus is respectively connected with the positive electrode plate and the negative electrode plate through leads, the positive electrode drug storage gel is arranged on the positive electrode plate, and the negative electrode electrolyte storage gel is arranged on the negative electrode plate.
Skin permeation test of isolated guinea pig
Adding 1.5g of the positive drug storage gel obtained in examples 1-6 into a supply chamber of a diffusion instrument, inserting an alloy material electrode, connecting an ion electro-osmosis instrument positive electrode, and sealing a pool opening; 5.5mL of transdermal receiving solution and a magnetic stirrer are added into the receiving chamber, an alloy material electrode is inserted, and the anode of an ion electro-penetrometer is connected. Starting the iontophoresis device, maintaining a constant current intensity of 0.17mA cm -2 1mL of the receiving solution was taken at 1,2, 4, 6, 8 and 10h with constant stirring at a constant temperature of 32 ℃ and supplemented with an equal amount of the blank receiving solution. The samples from the permeation experiments were filtered through a 0.22 μm disposable needle filter and analyzed by liquid chromatography, wherein the graphs of the permeation quantity of the isolated guinea pig skin accumulated drug versus time in examples 1-3 are shown in fig. 2, and the data were processed and analyzed as follows: the calculation formula of the unit area cumulative permeation quantity is as follows:
note: Q n The transdermal accumulated permeation quantity of the unit area of the nth sampling point is taken as the unit area; c n The drug concentration measured for the nth sampling point; v 0 Is the volume of the receiving chamber; c i The drug concentration measured for the ith sample point; v is the sampling volume; and A is the effective penetration area. In this experiment, V 0 ＝5.5ml，A＝0.71cm 2 ，V＝1mL。
The test results show that the positive electrode drug storage gel prepared in the above examples all show good ion electroosmosis applicability through 0.17 mA-cm -2 The current penetration promoting effect of the composition is that the cumulative penetration amount per unit area of 10h is 2081.7 +/-456.8, 1679.2 +/-454.6 and 1838.7 +/-372.7 mu g/cm -2 . Meanwhile, the positive drug reservoir gels of examples 4 to 6 also have good applicability to iontophoresis.
Pharmacokinetic testing of rats
Test method 1:
18 SD rats, 250 + -50 g in weight, were randomly and evenly divided into three groups. Effective action area of administration: the positive electrode and the negative electrode are both 2cm 2 (ii) a Dosage: 7.5mg (gel 1.5 g); current intensity, control: 0mA cm -2 (ii) a Low current group: 0.09mA/cm -2 (ii) a High current group: 0.17mA cm -2 . Rats were anesthetized for a short period of time by ether inhalation, their back and abdomen hairs were carefully removed, and the test was performed after 1 day of resting. The positive and negative reservoir gels of the iontophoresis transdermal drug delivery system prepared in example 2 were used, the electrode coated with the positive drug reservoir gel was attached to the back of the rat, the electrode coated with the negative reservoir electrolyte gel was attached to the abdomen of the rat, and the rat was placed in a stainless steel rat holder. Starting iontophoresis transdermal drug delivery system, adjusting and maintaining desired current intensity for 10 hr, removing electroosmosis and electrode slice, wiping off residual gel, collecting blood after 0.5, 1,2, 4, 8, 10, 12, 16, 24, and 34 hr after administration, anticoagulating with heparin, and centrifuging for 10min (6000 rpm. Min) -1 ) Plasma was separated and stored at-20 ℃ for testing. After treatment, liquid chromatography analysis is carried out.
2, test results:
the results of the TEH iontophoresis test are shown in Table 1 and FIG. 3. The amount of terazosin hydrochloride that penetrates the skin into the blood circulation in the absence of current was so low that it was not detectable by HPLC. At this time, the permeation promoting effect of applied current on TEH was significant (P < 0.05), and the high current group (0.17 mA cm) -2 ) And low current group (0.09 mA cm) -2 ) The main pharmacokinetic parameters of (a) are: AU (AU)C(0-t)：2493.7ng·mL -1 H and 5873.0ng mL -1 H; t1/2 (β): 11.4h and 10.1h; tmax:10h and 10h; cmax:135.3 ng/mL -1 And 292.6 ng. ML -1 。
TABLE 1 Primary pharmacokinetic parameters of TEH transdermal iontophoresis
Pharmacodynamic test of rat model with essential hypertension
Test method 1:
the influence of terazosin hydrochloride on the blood pressure of a primary hypertensive rat (SHR) is determined by adopting a method for non-invasive blood pressure measurement of the tail artery of the rat, and 10 normal awake male SHR rats with the body weight of 250 +/-50 g are randomly and averagely divided into two groups. Selecting a proper fixing frame according to the body weight, starting the instrument to preheat for about 20min, carrying out pressure signal calibration, leading the tail of a rat to be close to the root of the tail through a pressurizing sleeve, paying attention to the direction that the tail of the rat passes through the pressurizing sleeve, indicating the direction by an arrow on the pressurizing sleeve, adjusting the pressurizing sleeve of the tail of the rat to enable the instrument to detect the tail artery pulse signal, and dividing the experiment into two groups: control group, TEH gel ion electric penetration promoting group, no current loading, and administration dosage of 7.5mg/2.0cm 2 (ii) a TEH gel iontophoresis group, using iontophoresis transdermal drug delivery system prepared in example 4, current value was 0.17mA/cm 2 The administration dose is 7.5mg/2.0cm 2 . The iontophoresis transdermal drug delivery system was started, the desired current intensity was adjusted and maintained for 10h, the electroosmosis and electrode pads were subsequently removed, and the gel remaining on the skin was wiped off, and rat blood pressures, including Systolic Blood Pressure (SBP) Diastolic Blood Pressure (DBP), were measured before and at 2h, 4h, 6h, 8h, 12h, 24h, and 32h of administration, respectively.
2 results of the test
SHR rats were dosed with TEH gel at about 2mg/2cm 2 Then, compared with the no-current control group, the SHR rats which are promoted to penetrate by the current of 0.17mA have obvious blood pressure reducing effect (see table 2 and figure 4), the SBP and DBP of the SHR rats are remarkably reduced within 4h-10h of the iontophoresis period, and the SHR rats can continue to reach 2h after drug withdrawal (namely 12h time point))。
TABLE 2 Effect of TEH iontophoretic System on the blood pressure of SHR rats (n = 5)
Comparing with control group, and indicating P <0.05 and P <0.01
Pharmacodynamic test of rat model with prostatic hyperplasia
A rat prostatic hyperplasia model is prepared by a method of injecting testosterone propionate into a rat subcutaneously every day, and the prostatic hyperplasia condition of the rat is evaluated by measuring organ indexes of tissues and organs such as prostate, seminal vesicle gland and glandulae preputiales. The rats in each group were 6, half male and half female, and the experimental groups and administration were as follows:
normal group, i.e. normal reared rats;
model group, rats injected with testosterone propionate 3mg/kg subcutaneously every day;
gel group, rat removed North and abdomen hair, administered with iontophoresis transdermal drug delivery system gel prepared in example 4 at a dose of 2mg/2.0cm 2 Wherein the positive electrode reservoir gel is given to the back, the negative electrode reservoir gel is given to the abdomen, the positive electrode drug reservoir gel and the negative electrode electrolyte reservoir gel are replaced once a day at different positions, and meanwhile, 3mg/kg of testosterone propionate is injected subcutaneously every day;
in the low current group, the rat removed the hair from the north and the abdomen, and the iontophoresis transdermal drug delivery system gel prepared in example 2 was administered at an administration dose of 2mg/2.0cm 2 Wherein the back part is provided with gel of the positive electrode storage, the back part is connected with the positive electrode of the ion electro-osmosis apparatus, the abdomen part is provided with gel of the negative electrode storage, the back part is connected with the negative electrode of the ion electro-osmosis apparatus, the gel of the positive electrode medicament storage and the gel of the negative electrode electrolyte storage are replaced once a day at different positions, the back part is connected with the ion electro-osmosis apparatus to promote the permeation for 10 hours after each replacement, and the current density is 0.09mA/cm 2 Simultaneously subcutaneously injecting testosterone propionate at 3mg/kg every day;
high current group, administration dose 2mg/2.0cm 2 In rats, hair on north and abdomen was removed, and examples were given4, the prepared iontophoresis transdermal drug delivery system gel is characterized in that an anode storage gel is given to the back, an iontophoresis instrument anode is connected, a cathode storage gel is given to the abdomen, an iontophoresis instrument cathode is connected, the anode drug storage gel and the cathode electrolyte storage gel are replaced at different positions once a day, the iontophoresis instrument is connected after each replacement for promoting permeation for 10 hours, and the current density is 0.17mA/cm 2 Simultaneously subcutaneously injecting testosterone propionate at 3mg/kg every day;
on day 24, after anesthesia, the rats were sacrificed by removing their necks, the prostate, seminal vesicle and glandular tissues of the rats were removed, organ indexes were calculated, organ index = organ weight (g)/body weight (100 g), and the above organ indexes were compared for each group of rats.
The test result shows that compared with a normal rat, the prostate organ coefficient, the seminal vesicle coefficient and the glandular preputiales coefficient of the model group rat are all obviously increased (P is less than 0.05), which indicates that the modeling is successful; compared with the model group, the gel group has no inhibition effect on the prostatic hyperplasia of rats caused by the testosterone propionate, and the high-low current group and the low-high current group of the ion electro-osmosis group can obviously inhibit the prostatic hypertrophy of rats caused by the testosterone propionate.
TABLE 3 influence of TEH iontophoresis System on organ coefficients of testosterone propionate-induced prostatic hyperplasia rats (n = 6)
| Test group | Prostate coefficient (g/100 g) | Seminal vesicle coefficient (g/100 g) | Coefficient of preputial gland (g/100 g) |
| Normal group | 0.1203±0.0425 | 0.1531±0.0506 | 0.0172±0.047 |
| Model set | 0.2850±0.0792* | 0.2467±0.0759* | 0.0251±0.075* |
| Gel set | 0.2638±0.0741* | 0.2540±0.0644** | 0.0234±0.066* |
| Low current group | 0.1826±0.0537 #^ | 0.2055±0.0478 # | 0.0176±0.043 ##^ |
| High current group | 0.1569±0.0479 ##^ | 0.1892±0.0576 #^ | 0.0182±0.029 # |
P <0.05, P <0.01, compared to normal group;
in comparison with the set of models, # represents P<0.05， ## Represents P<0.01；
In comparison with the gel group, ^ represents P<0.05， ^^ Represents P<0.01。
Test of Effect of Current intensity on the rate of TEH iontophoresis
In vitro guinea pig skin permeation experiments were performed in groups 6 using iontophoresis transdermal administration prepared in example 5The medicinal gel maintains the current intensity of iontophoresis device at 0, 0.10, 0.20, 0.30, 0.39, and 0.49mA cm -2 Sampling is carried out for 1,2, 4, 6 and 10 hours after administration, liquid chromatography analysis is carried out, the concentration of the drug in the sample is calculated, and the osmotic kinetic characteristics of the TEH under different current intensities are inspected.
The cumulative permeation amount Q per unit area at each time point was calculated from the TEH concentration values measured at the different time points. The cumulative permeation at each current level was measured and then plotted as time t versus cumulative permeation Q to obtain the permeation kinetics curves for TEH at different current levels, the results of which are shown in fig. 4. Regression curve analysis is performed on the linear part of the osmotic kinetics curve, the steady-state permeation rate Jss of each experimental group and the corresponding permeation increase factor ER are calculated, and the obtained parameters are shown in figure 6.
From the above results, it was found that the steady state permeation rates of the current intensity groups were significantly different (P < 0.05), and when the current intensity was from 0.10mA cm -2 Gradually increased to 0.49mA cm -2 The steady state permeation rate increases with the increase of the current intensity, and is from 80.36 mu g-cm- 2 ·h -1 Increased to 304.93 mu g-cm- 2 ·h -1 The penetration enhancing effect of the current on the TEH is very significant, and the linear relation between the two is good (R = 0.986), but when the current intensity is increased to 0.4 mA-cm -2 In the above, the skin is burned.
Test of Effect of drug concentration on the rate of TEH iontophoresis
Based on the formulation process preparation of the positive drug storage gel of example 4, the proportions of terazosin hydrochloride were adjusted to account for 0.1%, 0.3%, 0.5%, 0.7% and 0.9% of the total TEH gel, respectively, and in vitro guinea pig skin permeation experiments were performed to adjust and maintain the output current intensity of the iontophoretic device at 0.49mA · cm -2 Sampling is carried out for 1,2, 4, 6, 8 and 10 hours after administration, liquid chromatography analysis is carried out, the concentration of the drug in the sample is calculated, and the osmotic kinetic characteristics of the TEH under different drug concentrations are inspected. The cumulative permeation amount Q per unit area at each time point was calculated from the TEH concentration values measured at the different time points. Make a return to the straight part of the osmotic kinetics curveAnd (4) performing curve analysis, and calculating the steady-state permeation rate Jss of each experimental group. FIG. 7 is a graph obtained by plotting the steady-state permeation rate Jss as the ordinate against the drug concentration.
Test results show that the TEH and the steady-state permeation rate are not in a linear relation, and when the concentration is less than or equal to 0.5%, the steady-state permeation rate is increased along with the increase of the concentration; when the concentration is more than or equal to 0.5%, the increase of the steady-state permeation rate is limited, and the Student t-test analysis is carried out by using Excel, so that no obvious difference (P is more than 0.05) exists between every two Jss (0.5%), jss (0.7%) and Jss (0.9%).
Test of Effect of drug depot pH on the rate of TEH iontophoresis
Based on the preparation of the positive drug depot gel formulation process of example 4, four batches of 0.5% teh gels were prepared by adjusting the drug depot gel pH to 4.8, 6.7, 7.4 and 8.1 with triethanolamine, respectively, where gel pH =4.8 is the initial pH value for the formulation without triethanolamine added. Then carrying out an in-vitro guinea pig skin permeation experiment, adjusting and maintaining the output current intensity of the iontophoresis device to be 0.49mA · cm < -2 >, sampling 1,2, 4, 6, 8 and 10 hours after administration, carrying out liquid chromatography analysis, calculating the drug concentration in the sample, and inspecting the permeation kinetic characteristics of TEH under different pH conditions. The cumulative permeation amount Q per unit area at each time point was calculated from the TEH concentration values measured at the different time points. And (4) performing regression curve analysis on a linear part of the osmotic kinetic curve, and calculating the steady-state permeation rate Jss of each experimental group and the corresponding permeability increasing times ER. FIG. 8 is a graph obtained by plotting the steady-state permeation rate Jss as the ordinate against the pH value.
The test results show that the drug reservoir pH has a significant effect on transdermal iontophoresis of TEH, and that the steady state permeation rate of TEH decreases as the pH increases from 4.8 to 8.1. The iontophoretic permeation-increasing factors of TEH at pH =6.7, pH =7.4 and pH =8.1 were 0.84, 0.44 and 0.29, respectively, with reference to the gel with pH = 4.8.
Effect of competitive salt NaCl concentration on TEH iontophoretic Rate
Based on the preparation of the positive drug reservoir gel formulation of example 4, the positive drug reservoir gel was introduced with the competitive salt NaCl (i.e. added to the formulation)NaCl) was added, and NaCl gel containing 0.1% of NaCl, 0.3% of NaCl, 0.5% of NaCl, and 1.0% of NaCl was prepared. Then carrying out skin permeation experiment of guinea pig in vitro, adjusting and maintaining the output current intensity of iontophoresis device to 0.49 mA-cm -2 Sampling is carried out for 1,2, 4, 6, 8 and 10 hours after administration, liquid chromatography analysis is carried out, the concentration of the drug in the sample is calculated, and the osmotic kinetic characteristics of TEH under different NaCl concentrations are inspected. The cumulative permeation amount Q per unit area at each time point was calculated from the TEH concentration values measured at the different time points. And (3) performing regression curve analysis on a linear part of the osmotic kinetics curve, calculating the steady-state permeation rate Jss of each experimental group and the corresponding permeability increasing times ER, and drawing a curve by using the steady-state permeation rate Jss as an ordinate to plot the NaCl concentration in the graph in FIG. 9.
The test results show that the competitive salt NaCl has a significant effect on transdermal iontophoresis of TEH. The steady state permeation rate of the NaCl-free TRH was the greatest, with the steady state permeation rate decreasing with increasing NaCl concentration in the gel formulation.
Claims (7)
1. An iontophoresis transdermal drug delivery system is characterized by comprising an iontophoresis instrument, a positive electrode plate, a negative electrode plate, a positive electrode drug storage gel and a negative electrode electrolyte storage gel, wherein the iontophoresis instrument is connected with the positive electrode plate and the negative electrode plate respectively through leads, the positive electrode drug storage gel is arranged on the positive electrode plate, and the negative electrode electrolyte storage gel is arranged on the negative electrode plate;
the positive electrode drug storage gel is prepared by the following method: weighing 0.1 to 7 percent of main medicine, 1.5 to 10 percent of excipient, 1 to 25 percent of humectant, 0.01 to 1 percent of pH regulator, 0.01 to 1 percent of preservative and 63 to 98 percent of first solvent according to the weight ratio; dissolving a humectant and a preservative in 56-97% of the weight of a first solvent, uniformly mixing, adding an excipient, uniformly dispersing to obtain a mixed solution, dissolving a main drug in the remaining amount of the first solvent, mixing the dissolved main drug with the mixed solution, swelling overnight, adjusting the pH to 4-10 by using a pH regulator, and finally centrifuging at 2000-100010 rmp for 5-30min to remove air bubbles to obtain an anode drug storage gel;
the negative electrode electrolyte reservoir gel is prepared by the following method: weighing 0.8 to 10 percent of excipient, 5 to 20 percent of humectant, 0.01 to 0.8 percent of preservative, 0.03 to 0.9 percent of pH regulator and 69 to 95 percent of second solvent according to the weight ratio, dissolving the humectant and the preservative in the second solvent, uniformly mixing, then adding the excipient, uniformly dispersing, regulating the pH to 4 to 8 by using the pH regulator, centrifuging at 2000 to 10000rmp for 5 to 30min, and removing air bubbles to obtain negative electrode electrolyte reservoir gel;
the main drug is terazosin hydrochloride or other medically acceptable salts of terazosin;
the current density used by the ion introduction instrument is 0.1 to 0.4mA-cm -2 。
2. The iontophoretic transdermal drug delivery system of claim 1, wherein the first solvent is ultrapure water.
3. The iontophoretic transdermal drug delivery system in claim 1, wherein the excipient comprises one or two of polyvinylpyrrolidone, hydroxypropyl cellulose, carbomer and polyvinyl alcohol mixed in any ratio.
4. The iontophoretic transdermal drug delivery system of claim 1, wherein the humectant is composed of one or two of 1, 2-propylene glycol and glycerin mixed in any ratio.
5. The iontophoresis transdermal drug delivery system in claim 1, wherein the pH regulator is one or two of triethanolamine and triethylamine, and the pH regulator is mixed in any ratio.
6. The iontophoretic transdermal drug delivery system of claim 1, wherein the preservative is one or more of ethylparaben, benzoic acid and salts thereof, sorbic acid and salts thereof, dehydroacetic acid and sodium salts, and parabens, mixed in any ratio.
7. The iontophoretic transdermal drug delivery system of claim 1, wherein the second solvent is a mixture of one or more of a phosphate buffer, an acetate buffer, a citric acid buffer, and a boric acid buffer in any ratio.
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