CN111084755A

CN111084755A - Benzodiazepine medicine composition for resisting febrile convulsion and intelligent transdermal delivery system thereof

Info

Publication number: CN111084755A
Application number: CN202010024307.0A
Authority: CN
Inventors: 陈勇; 凌勇; 朱丽; 刘季
Original assignee: Nantong University
Current assignee: Nantong University
Priority date: 2020-01-10
Filing date: 2020-01-10
Publication date: 2020-05-01
Anticipated expiration: 2040-01-10
Also published as: CN111084755B

Abstract

The invention provides an anticonvulsant pharmaceutical composition and a delivery system thereof based on a transdermal iontophoresis technology. A pharmaceutical composition for treating febrile convulsion comprises a benzodiazepine prodrug and a pharmaceutical adjuvant, wherein the benzodiazepine prodrug is a water-soluble ionizable precursor derivative prepared by chemically modifying a water-insoluble benzodiazepine compound which has 3-hydroxyl and is not dissociated at a physiological pH value; an intelligent transdermal delivery system of a benzodiazepine drug composition for resisting febrile convulsion is characterized in that direct current is utilized to rapidly and controllably transdermally administer an artificially ionized 3-hydroxybenzazepine compound derivative in a dosage manner, effective blood treatment concentration can be achieved in a short time, and febrile convulsion can be intervened effectively.

Description

Benzodiazepine medicine composition for resisting febrile convulsion and intelligent transdermal delivery system thereof

Technical Field

The invention belongs to the technical field of biological medicines, and relates to application of a benzodiazepine prodrug in preparation of an anti-heat convulsion medicine for transdermal iontophoresis, in particular to a benzodiazepine medicine composition for anti-heat convulsion and an intelligent transdermal delivery system thereof.

Background

Febrile convulsions (FS) are a common disease in infants and young children, with a prevalence of about 4%, most frequent in infants between 2 months and 5 years. FS is a common pediatric emergency and is also the most common pediatric neurological symptom, and is most frequently found within 24 hours after fever. The onset of FS symptoms is clear, and most of them are symptoms based on fever: such as temporary coma, neck rigidity, convulsion, binocular upsightedness, tooth closeness, loud scream, white foam in mouth, incontinence of stool and urine, etc. The continuous convulsion may damage the intelligence development of children patients, and even the sputum blocks the trachea to suffocate due to the convulsion of individual children patients.

Currently, Benzodiazepines (BDZ) are frequently used in clinic as a first-line medicament for preventing and relieving FS of infants. Oral solid formulations and injections are the main marketed dosage forms of BDZ drugs. However, due to the wide variation in infant physical development and disease onset, oral BDZ generally requires accurate dose titration and appropriate dose adjustment depending on the disease condition, which requires the destruction (dose division) of an originally complete formulation unit (e.g., a tablet or a capsule), which is not easy to quantify accurately in practice; in addition, oral administration of solid drugs to infants in the stage of FS onset also has compliance problems such as dysphagia. Intravenous or intramuscular BDZ injection is a rapid method of preventing or inhibiting FS, but administration by injection is also not easily achieved in the absence of sterile equipment and trained practitioners, especially when the FS occurs suddenly in infants and young children in daily life.

The transdermal delivery system of diazepam has been approved by the US FDA for marketing, the sublingual mucosa has low barrier function and abundant blood flow under mucosa, lorazepam sublingual tablets have been approved, so far, the transdermal delivery system of BDZ has no product on market, but there have been several studies, the transdermal delivery system is a drug delivery method which can release the drug gradually from transdermal preparation and be absorbed by skin into systemic circulation, some researchers have conducted studies on BDZ transdermal delivery system, the transdermal absorption rate is slow due to the barrier Effect of the stratum corneum of the skin, the requirement for treatment cannot be met, in order to enhance the transdermal absorption of drugs, the Schglia et al have been made in "the transdermal absorption of drugs is a very effective drug delivery system of a drug, the transdermal absorption rate is very slow, the requirement for treatment is not met," the drug delivery system is capable of increasing the transdermal absorption rate of a drug delivery system of a medicament in vivo and/or a transdermal delivery system of a patient, the transdermal absorption of a drug delivery system of a drug, the transdermal absorption rate is difficult to achieve, and the Effect of a therapeutic Effect of a drug delivery system of a drug in a small infant, a human body environment, a drug delivery system, a patient, a.

The Iontophoresis technology (ionophoresis) based on electrochemical theory is to increase the delivery rate of charged water-soluble drug molecules by applying a weak electric field. The ion leading-in system is mainly composed of a power supply, a connecting circuit, an electrode and a storage. The programming device may also be integrated into the iontophoresis system. The electrodes are composed of an anode and a cathode. The reservoir is comprised of a reservoir containing an ionized drug and a reservoir containing a conductive agent (e.g., a conductive gel). The positively charged drug (such as lidocaine hydrochloride) is contacted with the anode, the negatively charged drug (such as dexamethasone sodium phosphate) is contacted with the cathode, and the electrode is not contacted with the skin surface. When the current is switched on, the charged drug ions in the electric field between the anode and the cathode move directionally, i.e. an electromigration effect occurs, causing the drug to be "pushed" into the skin and further into the blood.

Iontophoresis has a number of advantages: firstly, as a non-invasive administration mode, as long as the current intensity is controlled within a certain range, the incidence rate of skin irritation is extremely low, and the compliance of patients is good; second, iontophoresis can increase the degree and rate of transdermal delivery of charged water-soluble drug molecules by orders of magnitude, and administration is rapid; third, by adjusting the current intensity and the introduction time, iontophoresis can precisely control the drug delivery kinetics, enabling dose titration and dose fine-tuning to be achieved. Transdermal iontophoresis technology, because of its advantages, has received considerable attention in the administration of drugs to children. For example, Djabri et al performed some prospective studies on Transdermal iontophoresis of phenobarbital and ranitidine for children in the two articles "Passive and ionotropic Transdermal delivery of phenobarbital: immunological in the dosage form" and "Transdermal ionotropic of antibiotic in the dosage form", respectively.

As mentioned above, iontophoresis is suitable for transdermal delivery of drug molecules that have some water solubility and can be ionized in aqueous solution (pH in a range acceptable for human skin). However, BDZ drugs are generally poorly water soluble and, based on drug pKa analysis, do not dissociate sufficiently to form charged ionized structures under dermatologically acceptable neutral or near neutral conditions, and thus, the physicochemical properties of BDZ drugs render them unsuitable for transdermal administration using iontophoresis, and other approaches to address this problem and prove their effectiveness are needed.

Disclosure of Invention

The invention provides a benzodiazepine medicine composition for resisting febrile convulsion and an intelligent transdermal delivery system thereof, and aims to solve the problems in the background art.

The embodiment of the invention provides a febrile convulsion resisting pharmaceutical composition which is characterized by comprising a benzodiazepine prodrug and a pharmaceutical adjuvant, wherein the benzodiazepine prodrug is prepared by chemically modifying-OH of a benzodiazepine compound with 3-hydroxy.

In a further embodiment, the benzodiazepine compound having a hydroxyl group in position 3 is oxazepam, temazepam, lorazepam and chlordiazepam, preferably lorazepam.

In a further embodiment, the benzodiazepine prodrug is an amino acid ester prepared by esterification of a benzodiazepine compound having a hydroxyl group at position 3 with a specific amino acid, including natural amino acids and unnatural amino acids, preferably glycine.

The embodiment of the invention also provides an intelligent transdermal delivery system of the benzodiazepine drug composition with the function of resisting the febrile convulsion, which is characterized in that the delivery mode is that a direct current or alternating current-based ion introduction patch is applied to the skin, a power supply is switched on, a positively charged benzodiazepine prodrug in a drug storage is delivered into blood circulation through the skin by utilizing the electromigration effect, the absolute dosage of the drug delivered into the systemic circulation can be effectively and accurately regulated by changing the current intensity and the acting duration of the current, and the individual administration is facilitated.

In a further embodiment, positively charged benzodiazepine prodrugs can be rapidly delivered transdermally under the action of an electric field, absorbed by dermal capillaries and then enter systemic circulation, where equimolar amounts of the active benzodiazepine drug and amino acids are released by in vivo chemical and enzymatic hydrolysis.

In a further embodiment, after transdermal administration of the formulations and delivery techniques listed in the present invention, the concentration of benzodiazepine drugs in the blood rapidly increases and reaches an effective therapeutic dose in a short time, exerting a therapeutic effect of intervening in febrile convulsions.

The invention has the advantages that when the infant whose thermoregulation center is immature can not be finished by oral administration and intravenous injection administration, the technology of the invention can be used for convenient and painless administration; also can be according to this patent technique further with the leading-in paster intellectuality of ion, the remote control of being convenient for is dosed, is applicable to the old person and other crowd insensitive to the time node of using medicine.

In certain embodiments, to ensure that BDZ drugs are able to be charged and exhibit good water solubility, it is desirable to prepare these BDZ drugs as prodrugs thereof. The "Prodrug" (produgs), also called Prodrug, etc., refers to a Prodrug having a biological activity of a Parent drug (Parent drug) which is obtained by modifying the chemical structure thereof and which is inactive or less active in vitro and releases the Parent drug in vivo by enzymatic or nonenzymatic conversion to exert the drug effect. The characteristics of a "prodrug" generally include three aspects: first, a "prodrug" should be inactive or less active than the parent drug; secondly, the parent drug and the modifying group are generally connected by covalent bonds, but can be cleaved in vivo to form the parent drug, and the process can be a simple acid and alkali hydrolysis process or an enzymatic conversion process; thirdly, the development of the prodrug has many purposes, such as increasing water solubility, increasing lipid solubility, improving bioavailability of the drug, increasing stability of the drug, reducing toxic and side effects, promoting long-acting of the drug and the like.

In certain embodiments, prodrugs of BDZ drugs are those that are modified by certain specific groups (e.g., hydroxyl groups) in the BDZ drug, linking groups that can be ionized under neutral or near neutral conditions through certain specific chemical bonds or atoms. In other embodiments, BDZ drugs need to be chemically modified by simple procedures to form water-soluble ionized BDZ prodrugs, followed by rapid and controlled transdermal delivery using iontophoresis. Such chemical modifications can be distinguished based on the substituents on the BDZ drug parent ring.

In certain aspects of the invention, the BDZ prodrug is stable in solution, but is rapidly and efficiently converted to the active form by esterase activity in the dermis. Thus, BDZ prodrugs can be efficiently delivered to tissue by transdermal iontophoresis and then rapidly converted to the pharmaceutically active form by enzymatic hydrolysis of the dermal layer.

In certain aspects of the invention, the anticonvulsant pharmaceutical composition further comprises a buffer system. Such as phosphate, carbonate, HEPES or TRIS buffer systems. Thus, in some embodiments, the pH of the febrile convulsion pharmaceutical composition is about, or at least about, or less than about 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.8.9, 8.9, 8.0, 8.3, 8.4, 8.5, 8.6, 8.8.8.9, 8.9, 9, or any derivable therein. In certain aspects of the invention, the pH of the anticonvulsant pharmaceutical composition is from about 5.0 to 8.0 or from about 5.5 to 7.8 or from about 6.0 to 7.5 or from about 6.4 to 7.0. In certain particular aspects, the pH of the anticonvulsant pharmaceutical composition is near physiological pH. In some aspects of the invention, the pH of the composition is adjusted to a range where at most a portion of the BDZ drug is charged or protonated.

In certain aspects of the present invention, the febrile convulsion pharmaceutical composition comprises pharmaceutically acceptable adjuvants, such as moisturizer, salt, preservative and/or anesthetic. For example, anesthetics such as lidocaine, bupivacaine, butacaine, chloroprocaine, cinchocaine, etidocaine, mepivacaine, prilocaine, ropivacaine, and/or tetracaine can be added to reduce discomfort during use of the current.

In certain aspects of the present invention, the febrile convulsion pharmaceutical composition comprises non-limiting examples of salts, such as sodium chloride, magnesium sulfate, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, or any other conductive salts, wherein certain salts also have a buffering effect.

In certain aspects of the invention, the anticonvulsant pharmaceutical composition comprises a moisturizer such as amino acids, chondroitin sulfate, diglycerol, erythritol, fructose, glucose, glycerol, glyceryl polymers, glycol, 1,2, 6-hexanetriol, honey, hyaluronic acid, hydrogenated honey, hydrogenated starch hydrolysates, inositol, lactitol, maltitol, maltose, mannitol, natural moisturizing factor, PEG-15 butylene glycol, polyglycerol sorbitol, pyrrolidone carboxylate, potassium PCA, propylene glycol, sodium glucuronate, sodium PCA, sorbitol, sucrose, trehalose, urea and xylitol, other examples include acetylated lanolin, acetylated lanolin alcohol, acrylate/acrylate C10-30 alkyl ester crosspolymer, acrylate copolymer, alanine, algae extract, aloe vera gel, galangal extract, aluminum starch octenyl succinate, aluminum stearate, coconut oil, linolenic acid, arginine aspartate, arnica extract, ascorbyl palmitate, palmitic acid, lanolin, camomile oil, lanolin fatty acid, sodium stearate, sodium stearyl alcohol stearate, sodium stearyl stearate, sodium stearate, glyceryl palmitostearate, glyceryl myristyl stearate, sodium stearate, glyceryl palmitostearate, sodium stearate, glyceryl palmitostearate, glyceryl stearate, glyceryl myristyl stearate, sodium stearate, glyceryl palmitostearate, sodium stearate, glyceryl palmitostearate, glyceryl stearate, glyceryl palmitostearate, sodium stearate, glyceryl palmitostearate, sodium stearate, glyceryl palmitostearate, glyceryl stearate, sodium stearate, glyceryl stearate, sodium stearate, glyceryl stearate, sodium stearate, glyceryl stearate, sodium stearate, PEG-2-glyceryl stearate, PEG-2-fatty alcohol stearate, PEG-sorbitan stearate, PEG-fatty alcohol stearate, PEG-fatty acid, PEG-2-polyoxyethylene stearate, PEG-sorbitan stearate, PEG-fatty acid, PEG-polyoxyethylene stearate, PEG-sorbitan stearate, PEG-polyoxyethylene stearate, PEG-fatty acid, PEG-sorbitan stearate, PEG-polyoxyethylene stearate, PEG-.

In certain aspects of the invention, the febrile convulsion pharmaceutical composition comprises non-limiting examples of antioxidants, such as acetylcysteine, ascorbic acid, ascorbyl polypeptide, ascorbyl dipalmitate, ascorbyl methylsiliconate pectin, ascorbyl palmitate, ascorbyl stearate, BHA, BHT, t-butylhydroquinone, cysteine hydrochloride, dimethylhydroquinone, di-t-butylhydroquinone, diethyl thiodipropionate, dioleyl tocopheryl methylsiliconate, disodium ascorbate, distearylthiodipropionate, thiodipropionate, dodecyl gallate, paeonoic acid, ascorbic acid ester, ethyl ferulate, ferulic acid, gallic acid, hydroquinone, isooctyl thioglycolate, kojic acid, magnesium ascorbate, magnesium ascorbyl phosphate, methylsiliconate ascorbic acid, natural plant antioxidants, such as green tea or grape seed extract, nordihydroguaiaretic acid, octyl gallate, phenylthioglycolic acid, potassium ascorbyl tocopheryl phosphate, potassium sulfite, propyl gallate, quinovone, rosmarinic acid, sodium ascorbate, sodium bisulfite, sodium erythorbate, sodium metabisulfite, sodium sulfite, superoxide dismutase, sodium thioglycolate, sorbylfurfural, thiodiglycol, thiodiethanolamide, thiodiglycolic acid, thioglycolic acid, thiolactic acid, thiosalicylic acid, tocopheryl polyether-5, tocopheryl polyether-10, tocopheryl polyether-12, tocopheryl polyether-18, tocopheryl polyether-50, tocopherol, soram, tocopheryl acetate, tocopheryl linoleate, vitamin E nicotinate, tocopheryl succinate and trisnonylphenoquinone phosphite.

In certain aspects of the present invention, the febrile convulsion pharmaceutical composition comprises non-limiting examples of preservatives, such as complex preservatives and/or phenoxyethanol, methylparaben, butylparaben, ethylparaben, propylparaben, and bactericides such as potassium sorbate and/or rosemary oil resin, and the like, as any of its components.

In certain aspects of the invention, the iontophoretic device used may include a device that is carried on the body during treatment. For example, the device may be affixed to a part of the body. Thus, in certain aspects, the device may include a power source that may be placed at a location remote from the treatment site, connected to the treatment site by a lead.

The febrile convulsion medicine composition can be prepared into various preparations. For example as a liquid, cream, ointment or gel. In some cases, the anticonvulsant pharmaceutical composition may be contained in a reservoir. In some cases, such a reservoir may be formed as a patch, such as a hydrogel patch. An important feature of the febrile convulsion pharmaceutical composition and the reservoir comprising the same is its ability to conduct electricity. Some examples of polymers that may be used as a typical reservoir or patch reservoir include, but are not limited to, water soluble polymers such as polyethylene oxide, polyvinyl pyrrolidone, polyvinyl alcohol, polyacrylamide, polyethylene glycol, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, and the like.

In certain aspects of the present invention, the anticonvulsant pharmaceutical composition is in the form of a patch. In certain embodiments, the patch is comprised of a water-soluble polymer. A patch comprising a water soluble polymer (e.g. as a matrix for a drug reservoir) will additionally comprise a water insoluble backing. For example, the patch of the present invention may be part of an "A + B" system, i.e., a patch that is a reusable device A plus a disposable water-soluble polymer drug reservoir B. Thus, the latter may be in contact with the skin, while the insoluble backing may be used to house the iontophoresis electrode and/or to protect the contents of the patch from the environment. Similarly, in such an integrated system, the patch backing may also isolate the drug reservoir from the electronic components in the controller (which may also have its own "housing"). Paster can utensilThere are various sizes and shapes. For example, the patch coverage area is less than about 100cm²Or less than about 10cm²Or less than about 5cm²。

In certain aspects of the present invention, after the febrile convulsion pharmaceutical composition is applied to the skin, an ion introduction current is applied to a designated transdermal region. In some cases, no greater than about 0.5mA/cm may be applied²The current density of (1). In some cases, no greater than about 0.4mA/cm may also be used². In certain aspects of the invention, about 0.01 to 0.5mA/cm is used²Or about 0.05 to 0.2mA/cm²The current density of (1). In some cases, the current may be applied for a period of time. For example, up to 4 hours or less, or up to 1 hour or less.

In certain embodiments, a water-soluble ionized BDZ prodrug of the invention is contained in a reservoir. In some versions, the reservoir is part of the electrode assembly, but in any case it is constructed of a conductive material that can be in contact with the electrodes. Such a reservoir is capable of delivering at least one drug through an application area on the skin of a patient. In some aspects, a reservoir of the present invention comprises a water-soluble polymer material that is capable of being electrically conductive with an electrode assembly. In a further embodiment, the water-soluble polymeric material is sufficiently tacky. In still further embodiments, the adhesive strength of the water-soluble polymer material to the electrode material is greater than the cohesive strength of the polymer material, and the cohesive strength is greater than the adhesive strength to the area of application. In other embodiments, the water soluble polymer is one or more of polyethylene oxide, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylamide, or polyethylene glycol. In other embodiments, the depot further comprises a vasoconstrictor, a stabilizer, and/or glycerol. In addition, the reservoir may contain additives and conductive salts, for example, glycerin, propylene glycol, polyethylene glycol, and/or preservatives may be contained in the reservoir.

The technical scheme of the invention has the following beneficial effects: the pharmaceutical composition prepared from the benzodiazepine prodrug (lorazepam prodrug) is proved to be capable of effectively interfering the generation of FS (soluble domain protein) at the level of rats by a series of verification modes of solubility, stability on the epidermis side and the dermis side, passive transdermal diffusion, iontophoresis transdermal delivery in vivo, oral administration and iontophoresis transdermal delivery contrast and transdermal iontophoresis by using gel, is expected to solve the problem of transdermal iontophoresis in the prevention or intervention of the FS of children in the future, and is particularly beneficial to clinical needs of individual treatment of the children.

The technical scheme of the invention has the following beneficial effects:

the high rate of recurrence and the serious risk of febrile convulsions in infants and young children are well recognized. The medicine is used effectively, accurately, timely and conveniently, and is the necessary principle of medicine for preventing febrile convulsion of infants. Because the body development of infants is very different, the medicine for children is different from that for adults, is not simply taken by children and the dosage is reduced, and particularly highlights the administration accuracy, safety and controllability while highlighting the compliance and convenience. The invention combines the BDZ medicament which is chemically modified with the iontophoresis technology for use, can accurately and controllably deliver the BDZ medicament with treatment amount into the body through the skin in a short time, provides a convenient and effective means for preventing infant febrile convulsion by using the medicament, and has obvious clinical advantages. Summarizing, the clinical advantages and innovativeness of the invention are shown in: (a) the medicine is not taken orally, so that the children patients are prevented from refusing to take the medicine; (b) the medicine is non-invasive, does not use an injection mode and does not need to be intervened by professional medical staff, so that the medicine can be effectively taken at the first time before the onset of febrile convulsion; (c) the invention can conveniently and accurately regulate and control the administration dosage intelligently according to the development condition and the disease condition of the sick children, and can realize individual accurate administration compared with the fixed dosage of oral administration and injection administration; (d) can rapidly and sufficiently deliver therapeutic doses of the drug to rapidly reverse febrile convulsions.

The novelty, feasibility and therapeutic advantages of the delivery method described in this patent are illustrated by the following figures and several examples, which are provided for the purpose of illustrating the benzodiazepine drug Lorazepam (LZP) and its water-soluble ionizable prodrug lorazepam glycinate (LZP-Gly).

Drawings

FIG. 1 is a scheme of synthesis of lorazepam glycinate (LZP-Gly);

FIG. 2 is a scheme of synthesis of lorazepam phenylalanine ester (LZP-Phe);

FIG. 3 is a scheme of synthesis of lorazepam isoleucine ester (LZP-Ile);

FIG. 4 is a graph of the stability of various lorazepam prodrugs; wherein, figure 4A is the stability of various lorazepam prodrugs in contact with the epidermal side over 0-6 h; FIG. 4B is the stability of various lorazepam prodrugs in contact with the dermal side over 0-120 min;

FIG. 5 is a graph of passive transdermal absorption of lorazepam and various lorazepam prodrugs;

FIG. 6 is a diagram of an experimental device for iontophoresis transdermal delivery in accordance with the present invention;

FIG. 7 is a graph of the iontophoretic transdermal delivery of lorazepam and various lorazepam prodrugs;

FIG. 8 is a diagram showing an apparatus for conducting an in vivo ion introduction experiment using rats in the present invention;

FIG. 9 is a graph of LZP plasma concentration of rat after introduction of LZP-Gly in vivo;

FIG. 10 is a graph comparing blood plasma levels of LZP following oral administration of LZP and iontophoretic transdermal delivery of LZP-Gly;

FIG. 11 is a pharmacodynamic graph of transdermal iontophoresis LZP-Gly according to the present invention; wherein, FIG. 11A is a pharmacodynamic graph of iontophoresis using a blank gel; FIG. 11B is a pharmacodynamic graph of iontophoresis using LZP-Gly gel.

Detailed Description

In order to make the technical problems, technical solutions and advantages to be solved by the present invention clearer, the following detailed description is given with reference to specific embodiments.

Example 1

Synthesis of LZP-Gly: weighing lorazepam (LZP, 0.50g, 1.56mmol), 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (EDCI, 0.48g, 3.10mmol), 4-dimethylaminopyridine(DMAP, 0.10g, 0.78mmol), Boc-glycine (Boc-Gly, 0.33g, 1.89mmol) was dissolved in 30ml Dichloromethane (DCM) and stirred magnetically at RT overnight. The reaction was monitored by thin layer chromatography. After the reaction, the precipitate was removed by filtration and the solution was spin-dried. The residue was redissolved in ethyl acetate and washed with water (2X 30ml), saturated NaHCO₃The solution (2X 30ml) and a saturated NaCl solution (1X 30ml) were washed successively. The organic layer was dried over anhydrous MgSO₄Drying, filtering and spin-drying the solvent. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate 4: 1). The eluent of the product is collected and spin-dried. The purified material was taken in a flask, and 5ml DCM and 5ml trifluoroacetic acid (TFA) were added sequentially and magnetically stirred for 2h under ice bath conditions. After the solvent is dried by spinning, the final product LZP-Gly is obtained. The yield thereof was found to be 78%. The synthetic route is shown in figure 1.

The compound structure is characterized as follows:¹H NMR(400MHz,DMSO)δ11.41(s,1H,NH),7.73–7.70(m,1H,Ar-H),7.61–7.52(m,4H,Ar-H),7.37(d,J＝8.8Hz,1H,Ar-H),7.02(d,J＝1.8Hz,1H,Ar-H),6.06(s,1H,CH),4.13(q,J＝17.4Hz,2H,CH₂)。¹³C NMR(100MHz,DMSO)δ167.42,164.95,164.48,137.27,133.14,132.38,132.26,131.86,130.42,128.98,128.05,124.10,86.42。

example 2

Synthesis of LZP-Phe: LZP (0.77g, 2.40mmol), EDCI (0.75g, 4.84mmol), DMAP (0.15g, 1.23mmol) and Boc-phenylalanine (Boc-Phe, 0.77g, 2.91mmol) were weighed out and dissolved in 30ml DCM and stirred magnetically at RT overnight. The reaction was monitored by thin layer chromatography. After the reaction, the precipitate was removed by filtration and the solution was spin-dried. The residue was redissolved in ethyl acetate and washed with water (2X 30ml), saturated NaHCO₃The solution (2X 30ml) and a saturated NaCl solution (1X 30ml) were washed successively. The organic layer was dried over anhydrous MgSO₄Drying, filtering and spin-drying the solvent. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 3: 1). The eluent of the product is collected and spin-dried. The purified material was taken in a flask, and 5ml DCM and 5ml TFA were added in sequence and magnetically stirred for 2h under ice bath condition. After spin-drying of the solvent, LZP-Phe was obtained as the final product. The yield thereof was found to be 73%. The synthetic route is shown in FIG. 2.

The compound structure is characterized as follows:¹H NMR(400MHz,DMSO)δ7.71–7.69(m,1H,Ar-H),7.63(d,J＝7.0Hz,1H,Ar-H),7.58–7.52(m,3H,Ar-H),7.35–7.26(m,5H,Ar-H),7.22(d,J＝7.0Hz,1H,Ar-H),7.01–7.00(m,1H,Ar-H),5.89(s,1H,CH),3.80–3.77(m,1H,CH),3.19–3.14(m,1H,CH₂),2.86–2.81(m,1H,CH₂)。¹³C NMR(101MHz,DMSO)δ174.70,165.06,164.89,138.35,137.65,137.21,132.26,130.34,130.13,129.96,128.97,128.71,128.63,128.39,128.03,127.91,85.30,55.95。

example 3

Synthesis of LZP-Ile: LZP (0.90g, 2.80mmol), EDCI (0.90g, 5.61mmol), DMAP (0.17g, 1.39mmol) and Boc-isoleucine (Boc-Ile, 0.79g, 3.40mmol) were weighed out and dissolved in 30ml Dichloromethane (DCM) and stirred magnetically at RT overnight. The reaction was monitored by thin layer chromatography. After the reaction, the precipitate was removed by filtration and the solution was spin-dried. The residue was redissolved in ethyl acetate and washed with water (2X 30ml), saturated NaHCO₃The solution (2X 30ml) and a saturated NaCl solution (1X 30ml) were washed successively. The organic layer was dried over anhydrous MgSO₄Drying, filtering and spin-drying the solvent. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 3: 1). The eluent of the product is collected and spin-dried. The purified material was taken in a flask, and 5ml DCM and 5ml TFA were added in sequence and magnetically stirred for 2h under ice bath condition. After the solvent is dried by spinning, the final product LZP-Ile is obtained. The yield thereof was found to be 68%. The synthetic route is shown in FIG. 3.

The compound structure is characterized as follows:¹H NMR(400MHz,DMSO)δ7.71–7.70(m,1H,Ar-H),7.62(d,J＝7.1Hz,1H,Ar-H),7.58–7.52(m,3H,Ar-H),7.33(d,J＝8.7Hz,1H,Ar-H),6.99(d,J＝2.3Hz,1H,Ar-H),5.87(s,1H,CH),3.42(d,J＝4.8Hz,1H,CH),1.91(s,1H,CH),1.79–1.77(m,1H,CH₂),1.70–1.54(m,1H,CH₂),0.97(d,J＝6.8Hz,3H),0.90–0.87(m,3H,CH₃)。¹³C NMR(101MHz,DMSO)δ175.01,172.56,164.97,137.65,137.25,132.26,130.32,128.92,128.68,128.33,128.02,127.87,85.23,56.51,19.13,15.97,12.18。

example 4

Solubility study: measuring appropriate amount of distilled water, adding excessive LZP, LZP-Gly, LZP-Phe or LZP-Ile, respectively, placing on magnetic stirrer, setting temperature at 37 deg.C, and stirring for 24 hr to obtain saturated solution of LZP, LZP-Gly, LZP-Phe or LZP-Ile. After the solution was filtered through a 0.45 μm microfiltration membrane, the subsequent filtrate was diluted to an appropriate volume, analyzed by HPLC injection, and the peak area was recorded to calculate the saturated solubility of LZP, LZP-Gly, LZP-Phe or LZP-Ile in water.

The results show that the solubility of all three prodrugs of LZP is improved to different extents compared to LZP, with LZP-Gly having the highest solubility, and LZP-Gly having a solubility about 60 times higher than LZP as calculated on the amount of substance (i.e. molar amount) (table 1). The increase in aqueous solubility indicates that poorly water soluble LZP can be converted to the water soluble LZP prodrug by prodrug engineering; further, because of the formation of the amino acid ester, the amino group inherent to the amino acid can be dissociated in a neutral or dermatologically acceptable, weak acid environment to provide a water-soluble ionized LZP prodrug for ease of iontophoretic administration.

TABLE 1, LZP and LZP solubility of prodrugs

Example 5

Stability study: a test solution of LZP prodrug at a concentration was prepared using MES buffer (10mM, pH 5.5). Stability of the prodrug when contacted the epidermal side of the skin was determined: washing the fresh pig ear skin with normal saline, fixing the pig ear skin with the epidermis facing upwards in vertical Franz diffusion cell (effective area of 2 cm)²) No liquid is added to the receiving tank. LZP-Gly, LZP-Phe or LZP-Ile solutions (1mM, 1mL) were added to the feed reservoir, and immediately started the timer, samples were taken every 15min, and after appropriate dilution, the amount of each prodrug and LZP was determined, and the remaining percentage of LZP-Gly, LZP-Phe or LZP-Ile, respectively, was calculated (n ═ 3). Stability of the prodrug when contacted the dermal side of the skin was determined: cleaning the pre-treated pig ear skin with normal saline, placing the pig skin dermis side up, fixing with vertical Franz diffusion cell (effective area is 2 cm)²) No liquid is added to the receiving tank. In the supply tankLZP-Gly, LZP-Phe, or LZP-Ile solutions (100. mu.M, 1mL) were added, timing was started immediately, samples were taken every 15min, and after appropriate dilution, the amount of each prodrug and LZP was determined, and the remaining percentage of LZP-Gly, LZP-Phe, and LZP-Ile, respectively, was calculated (n ═ 3). All experiments were performed under water bath conditions (32 ℃).

The results show that each LZP prodrug had no significant degradation within 2h when exposed to the epidermal side; on contact with the dermal side, various degrees of degradation of each prodrug occurred, due to the presence of large amounts of non-specific hydrolytic enzymes in the dermis of the skin, which catalyzed the hydrolysis of LZP prodrug and release LZP (fig. 4). LZP the prodrug, when in contact with the epidermal side of the skin, is in direct contact with the stratum corneum, where there is substantially no distribution of hydrolytic enzymes. It can be judged that the LZP pro-drug with positive charge can be rapidly delivered transdermally under the action of electric field, enters systemic circulation after being absorbed by dermal capillaries, and releases equimolar amounts of active benzodiazepine drugs and amino acids through in vivo chemical hydrolysis and enzymatic hydrolysis in the process.

Example 6

Passive transdermal diffusion: cleaning the skin of pig ear with normal saline, and using two-arm vertical Franz diffusion cell (effective diffusion area of 2 cm)²) The skin is held between the supply reservoir and the receiving reservoir with the epidermis side up. A magnetic stirrer and 12mL of PBS buffer (pH 7.4) were added to the receiving cell to ensure that no air bubbles were present between the dermal side of the skin and the receiving solution. The diffusion pool is placed in a constant-temperature circulating water transdermal diffusion instrument, the receiving pool is mostly immersed below the water surface, the temperature is controlled to be 32 ℃, and the rotating speed is 200 rpm. Before the start of the experiment, 1mL of physiological saline was added to the supply cell, the supply cell was equilibrated for 30min, the physiological saline was aspirated by a pipette, the supply cell was washed 3 times with pure water, and 1mL of a saturated LZP solution, a saturated LZP-Gly solution, a saturated LZP-Phe solution, or a saturated LZP-Ile solution was added to the supply cell, and 0.8mL of the solution was sampled from the receiving cell per hour while supplementing an equal volume of a receiving solution (PBS buffer), and the experiment was continued for 6 hours. The cumulative transdermal delivery was calculated using HPLC to determine the corresponding prodrug content and LZP content in the sink samples (n-6).

The results showed that LZP prodrug was not detected in the sink, only LZP, indicating that the LZP prodrug was degraded by the dermal hydrolytic enzymes in the skin and released LZP. After the saturated LZP solution is passively subjected to transdermal diffusion for 6 hours, no LZP molecules are detected in the diffusion cell; after 6h of passive transdermal diffusion of the saturated LZP prodrug solution, the solution was detected in LZP sink, wherein the transdermal diffusion of the saturated LZP-Gly solution was the greatest. This is primarily because all saturated LZP prodrug solutions have a greater concentration gradient difference than saturated LZP solutions and therefore diffuse more rapidly; in contrast, the solubility of LZP-Gly was the greatest among the three saturated LZP prodrug solutions, resulting in the highest concentration gradient difference among the saturated LZP-Gly solutions, and thus the highest diffusion rate (fig. 5).

Example 7

Iontophoresis transdermal delivery: cleaning the pre-treated pig ear skin with normal saline, and spreading the skin tissue in a diffusion cell (effective diffusion area of 2 cm)²) Fixed with the epidermis side up. 20mL and 12mL PBS buffer (pH 7.4) were added to the anode and receiving cells (also as cathode cells), respectively, with the receiving cells being continuously magnetically stirred (200 rpm). The diffusion pool is placed in a constant-temperature circulating water transdermal diffusion instrument, most of the receiving pool is immersed below the water surface, and the temperature is controlled to be 32 ℃. In order to reduce the competition of the same ions in the ion introduction process, a physically separated anode cell and a supply cell were connected by a salt bridge (formed by dissolving agarose with a mass fraction of 3% in a 0.1M NaCl solution and injecting the solution into a silicone tube for cooling and solidification). And respectively inserting the Ag electrode and the AgCl electrode into the anode pool and the receiving pool. The setup of the device is shown in fig. 6. Before the start of the experiment, 1mL of physiological saline was added to the well, the solution was equilibrated for 30min, then aspirated by a pipette, the well was washed 3 times with pure water, and LZP-Gly, LZP-Phe or LZP-Ile solutions (each having a concentration of 3mM and 1mL) were added to the well, respectively. LZP saturated solution (1mL) was used as a control. The DC power supply is turned on to start the experiment, and the current intensity is set to be 0.5mA/cm²0.8mL of the receiving well was sampled every hour while supplementing an equal volume of receiving solution (PBS buffer) and the experiment lasted 6 h. The cumulative transdermal delivery was calculated using HPLC to determine the corresponding prodrug content and LZP content in the sink samples (n-6).

The results showed that the transdermal absorption increased somewhat, but not significantly, when the saturated LZP solution was used for iontophoresis, and LZP was not detected in the receiving cell particularly 4 hours after initiation of iontophoresis, indicating that the lag time was long. No LZP prodrug was detected in the receiving reservoir upon iontophoresis of LZP prodrug, only LZP was detected, indicating that both LZP prodrug was enzymatically cleaved and LZP was released during iontophoresis, and that the amount of LZP in the receiving reservoir was much greater than the amount of LZP found in the receiving reservoir upon iontophoresis of a saturated LZP solution. This result demonstrates that the LZP prodrug has a better molecular formula as a substrate molecule suitable for transdermal iontophoresis than the poorly soluble non-ionized LZP molecule, of which LZP-Gly is most efficiently iontophoretically delivered, and has been shown to be the preferred LZP prodrug suitable for transdermal iontophoresis (fig. 7).

Example 8

LZP-Gly formulation composition

(a) LZP-Gly solution was prepared at a concentration of 3 mM.

Raw materials	Quality of
		LZP-Gly	0.015g
2- (N-morpholino) ethanesulfonic acid (MES)	0.02g
		NaOH	Proper amount of

Water was added to 10 ml.

The preparation method comprises the following steps: measuring the amount of water according to the prescription, placing the water into a beaker, adding the MES according to the prescription, stirring the mixture until the MES is dissolved, adding a proper amount of NaOH to adjust the pH of the solution to 5.5, finally adding LZP-Gly according to the prescription, stirring the mixture evenly, filtering the mixture by a 0.22 mu m filter membrane, and taking the subsequent filtrate to obtain the aqueous emulsion.

(b) LZP-Gly was prepared as a saturated aqueous solution.

Raw materials	Quality of
		LZP-Gly	0.07g
Sodium sulfite	0.01g

Water was added to 10 ml.

The preparation method comprises the following steps: measuring the amount of water according to the prescription, placing the water into a beaker, adding LZP-Gly according to the prescription, stirring until the medicine is not dissolved, filtering by a 0.22 mu m filter membrane, and taking the subsequent filtrate, namely LZP-Gly saturated aqueous solution.

(c) A carbomer gel of LZP-Gly was prepared.

Raw materials	Quality of
		LZP-Gly	0.06g
Carbomer	0.1g
		Benzyl alcohol	0.05g
Glycerol	0.1g
		Ethylenediaminetetraacetic acid sodium salt	0.02g
Triethanolamine	Proper amount of

Water was added to 10 ml.

The preparation method comprises the following steps: measuring a prescribed amount of water, placing the water in a beaker, adding LZP-Gly, glycerol, benzyl alcohol and ethylenediamine sodium acetate in a prescribed amount, stirring uniformly until the materials are dissolved, then adding carbomer to a water bath kettle at 30 ℃ for swelling for 30min, finally adding triethanolamine, and stirring to obtain LZP-Gly carbomer gel.

(d) Preparation of LZP-Gly HEC gel

Raw materials	Quality of
		LZP-Gly	0.06g
HEC	1g
		Propylene glycol	0.1g
Hydroxyphenyl Ethyl ester	0.02g
		Ethanol	2ml

Water was added to 10 ml.

The preparation method comprises the following steps: weighing a small amount of water in a beaker, adding LZP-Gly and propylene glycol in the amount of a prescription, uniformly stirring until dissolving, then adding HEC to a water bath kettle at 30 ℃ for swelling for 30min, stirring to obtain LZP-Gly HEC gel, dissolving ethylparaben in ethanol, adding into gel matrix under stirring, adding distilled water to a sufficient amount, and uniformly stirring to obtain the gel.

(e) Preparation of LZP-Gly HEC gel

Raw materials	Quality of
		LZP-Gly	0.06g
HEC	0.7g
		Glycerol	0.1g
Chlorobutanol	0.02g

Water was added to 10 ml.

The preparation method comprises the following steps: measuring a prescribed amount of water, placing the water in a beaker, adding LZP-Gly, glycerol and chlorobutanol in a prescribed amount, stirring uniformly until the mixture is dissolved, then adding HEC to a water bath kettle at 30 ℃ for swelling for 30min, and stirring to obtain LZP-Gly HEC gel.

Example 9

LZP pharmacokinetics after transdermal administration in rats: SD rats were taken and weighed approximately 250 + -20 g, and the rats were fasted but not water-deprived 12h before the start of the experiment. Before administration, pentobarbital sodium is injected into the abdominal cavity to anaesthetize the rat, then carotid artery intubation is carried out, the abdominal part of the rat is shaved, an ion introducing device is built, a PBS solution is used as an anode pool and is connected with an administration pool through a salt bridge, saturated LZP-Gly aqueous solution (1mL) is added into the administration pool, a PBS solution is used as a cathode pool (the salt bridge and an electrode are not directly contacted with the skin), and the direct current intensity is respectively set to be 0.5, 0.36 or 0.09mA/cm 2. The device set-up is shown in figure 8. And (3) after electrification, taking 0.3mL of blood at a preset time point, supplementing equivalent volume of heparinized physiological saline, quickly centrifuging the blood sample, taking supernatant, and immediately storing in a refrigerator at the temperature of-20 ℃ for testing. And (5) removing the device after electrifying for 5 h. Prodrugs and LZP were assayed in blood samples using UPLC-MS/MS.

The results showed that LZP-Gly was not detected in rat blood and only LZP was detected, indicating that LZP-Gly could be enzymatically cleaved and released LZP during introduction of body ions. When a fixed current intensity is applied, the LZP blood concentration gradually increases along with the increase of time; at a certain fixed time point, the blood concentration of LZP increases as the current intensity increases. The results are shown in FIG. 9. This result demonstrates that the present technology can effectively and precisely adjust the absolute amount of drug delivered into systemic circulation by varying the current intensity and duration of current action, facilitating individualized dosing.

Example 10

Comparison of oral LZP and transdermal delivery LZP-Gly: LZP-Gly was weighed and dissolved in water, hydroxyethyl cellulose (HEC) was added to the solution in a prescribed amount, and swelling was carried out at 45 ℃ for 20min to prepare LZP-Gly gel (containing 12mM LZP-Gly and containing 7% HEC). SD rats were taken and weighed approximately 250 + -20 g, and the rats were fasted but not water-deprived 12h before the start of the experiment. Before administration, pentobarbital sodium is injected into abdominal cavity to anaesthetize the rat, then carotid artery intubation is carried out, the rat abdomen is shaved, an ion introducing device is built, a PBS solution is used as an anode pool and is connected with an administration pool through a salt bridge, LZP-Gly gel of 1.5g is added into the administration pool, and a loop is formed by pasting an electrode patch on the lower limb. The current intensity was set at 0.5mA/cm 2. And (3) after electrification, taking 0.3mL of blood at a preset time point, supplementing equivalent volume of heparinized physiological saline, quickly centrifuging the blood sample, taking supernatant, and immediately storing in a refrigerator at the temperature of-20 ℃ for testing. And (5) removing the device after electrifying for 1 h. 0.5% CMC-Na solution was prepared, and a commercially available LZP tablet (specification: 1mg) was ground and pulverized to prepare a suspension, and 0.5mL (dose 2mg/kg) was administered per rat by gavage. 0.3mL of blood is taken at a preset time point, the blood sample is rapidly centrifuged, and the supernatant is immediately stored in a refrigerator at-20 ℃ for testing. After the experiment was completed, the blood samples were processed. The content of LZP-Gly and LZP in the sample was determined using UPLC-MS/MS.

The results showed that LZP-Gly was not detected in rat blood and only LZP was detected, indicating that LZP-Gly could be enzymatically cleaved and released LZP during introduction of body ions. When the transdermal iontophoresis is carried out for 1h, although the LZP peak concentration is lower than that of the oral administration LZP, the LZP blood concentration can be maintained at a higher concentration level within a certain period of time, and the protection effect on rats is better realized for a longer time. The results are shown in FIG. 10. This result demonstrates that transdermal iontophoresis LZP-Gly can rapidly deliver therapeutic amounts of LZP into the body, although peak concentrations are not as good as oral LZP, but because the drug forms a "drug depot" like pattern in the skin during transdermal administration, the drug is still slowly released from the skin even after the current is stopped, maintaining the plasma concentration more smoothly over a period of time than oral administration, facilitating the protection of animals from convulsions for a longer period of time.

Example 11

Pharmacodynamics: SD rats of 20 days old, half male and female, after three days of acclimation, 6 rats were randomly selected as a blank control group, and other rats were started at 23 days old for febrile convulsion induction modeling (12 h before modeling, rats started to fast but not to be watered), by the following method: weighing rat, heating in water bath, measuring with thermometer, heating to 45 deg.CEnsure that it is maintained at 45 ℃; placing a rat in a water bath pot, wherein the head of the rat is upward, the neck of the rat is immersed in water to prevent the rat from jumping out, and timing is started, and the hot water bath time is not more than 5 min; observing the state of the rat in water, recording time points and taking out the rat to a drying cage when the rat is in a tic state, observing the state and symptoms of the rat, recording the convulsion duration of the rat, and recovering consciousness when the rat touches the face. The blank control group was induced in the same manner, and the temperature of the hot water bath was controlled at 37 ℃. Inducing every other day according to the operation method for 5 times, wherein if convulsion frequency is more than or equal to 4 times within 5min, the convulsion is included in the experiment, otherwise, the convulsion is removed. 6 rats which are successfully molded are taken, the abdomen and the legs of the rats are shaved, an ion introduction device is built, a PBS solution is taken as an anode pool and is connected with a drug administration pool through a salt bridge, the abdomen of the rats is adhered with the drug administration pool, 1.5g of LZP-Gly gel is added into the drug administration pool, and the legs of the rats are adhered with electrode patches to form a loop. The current intensity was set at 0.5mA/cm²The administration time is 40min, after the administration is finished, the device is removed, the medicine-containing gel on the abdomen of the rat is wiped off, the febrile convulsion model is immediately induced according to the previous method, and the symptoms are recorded. Blank gels were used as controls. The classification of epileptic symptoms is shown in table 2.

The results show that the secondary FS seizures in rats can be effectively protected by transdermal iontophoresis using LZP-Gly gel for only 40min, and that the zheng score for epilepsy is much lower than that of the group using the blank gel for iontophoresis. Indicating that the ion introduction LZP-Gly can effectively interfere the FS in a short time. The results are shown in FIG. 11.

TABLE 2 grading of epileptic symptoms

While the foregoing is directed to the preferred embodiment of the present invention, it will be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention as defined in the appended claims.

Claims

1. The pharmaceutical composition for resisting febrile convulsion is characterized by comprising a benzodiazepine prodrug and a pharmaceutical adjuvant, wherein the benzodiazepine prodrug is prepared by chemically modifying-OH of a benzodiazepine compound with 3-hydroxy.

2. The pharmaceutical composition for relieving febrile convulsion of claim 1, wherein said benzodiazepine compound having hydroxyl group at position 3 is oxazepam, temazepam, lorazepam and chlordiazepam.

3. The anticonvulsant pharmaceutical composition of claim 2, wherein the benzodiazepine compound having a hydroxyl group at position 3 is lorazepam.

4. The anticonvulsant pharmaceutical composition of claim 1, wherein the benzodiazepine prodrug is an amino acid ester prepared by esterification of a benzodiazepine compound having a hydroxyl group at position 3 with a specific amino acid, the amino acid including natural amino acids and unnatural amino acids.

5. The anticonvulsant pharmaceutical composition of claim 4, wherein said amino acid is glycine.

6. An intelligent transdermal delivery system of a benzodiazepine drug composition with an anti-febrile convulsion function is characterized in that the delivery mode is an ion introduction patch based on direct current or alternating current, after the patch is applied to the skin, a power supply is turned on, a positively charged benzodiazepine prodrug in a drug storage is delivered into blood circulation through the skin by utilizing an electromigration effect, the absolute dosage of the drug delivered into the systemic circulation can be effectively and accurately adjusted by changing the current intensity and the duration of current action, and individualized administration is facilitated.

7. The system of claim 6, wherein the positively charged prodrug of benzodiazepine is rapidly delivered transdermally by an electric field, absorbed through dermal capillaries and enters systemic circulation, where equimolar amounts of active benzodiazepine drug and amino acids are released by chemical and enzymatic hydrolysis in vivo.

8. The system for smart transdermal delivery of a febrile convulsion benzodiazepine drug composition of claim 6, wherein after transdermal administration, the concentration of benzodiazepine drug in blood increases rapidly and reaches an effective therapeutic dose in a short time, exerting therapeutic effect of intervening febrile convulsion.

9. The system for the intelligent transdermal delivery of febrile convulsion benzodiazepine pharmaceutical composition of claim 6, wherein the infant whose thermoregulatory center is immature can be administered conveniently and painlessly when both oral and intravenous administration is not completed.

10. The system for the intelligent transdermal delivery of a febrile convulsion benzodiazepine pharmaceutical composition of claim 6, wherein the introduction of ions into the patch is intelligent and remotely controlled.