CN111529489A - Nasal spray containing diazepam - Google Patents
Nasal spray containing diazepam Download PDFInfo
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- CN111529489A CN111529489A CN202010303079.0A CN202010303079A CN111529489A CN 111529489 A CN111529489 A CN 111529489A CN 202010303079 A CN202010303079 A CN 202010303079A CN 111529489 A CN111529489 A CN 111529489A
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- nasal spray
- diazepam
- epilepsy
- nasal
- patients
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K9/0043—Nose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/12—Aerosols; Foams
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
Abstract
The invention provides a nasal spray containing diazepam, which consists of diazepam, a solvent, a penetration enhancer, an antioxidant and a bacteriostatic agent. Can be administered by nasal spray for treating recurrent epilepsia.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a diazepam-containing nasal spray.
Background
Epilepsy is a chronic disease in which there is a sudden abnormal firing of cerebral neurons, resulting in transient cerebral dysfunction. According to the latest Chinese epidemiological data, the total prevalence rate of domestic epilepsy is 7.0 per thousand, the annual incidence rate is 28.8/10 ten thousand, and the prevalence rate of active epilepsy with attacks within 1 year is 4.6 per thousand. Therefore, about 900 million epilepsy patients are estimated in China, 500-600 million of the epilepsy patients are active epilepsy patients, about 40 million epilepsy patients are newly added every year, and epilepsy has become the second most common disease of the neurology department, second to headache in China.
Epilepsy is seen in all age groups. The children have higher epilepsy incidence rate than adults, and the epilepsy incidence rate is reduced with the increase of the age. The incidence of epilepsy is rising again in the elderly due to cerebrovascular disease, senile dementia and degenerative changes of nervous system.
Epilepsy is a chronic disease, and although the epilepsy has little influence on patients in a short period, the long-term frequent seizures can cause the physical, mental and intelligence of the patients to have serious influence. The method mainly comprises the following steps: 1. the hazard of life: epileptics often have sudden attacks at any time, place and environment and without self control, and are easy to fall injury, scald, drowning, traffic accidents and the like. 2. Mental harm, which is often distinguished by society, causes difficulties in employment, marriage, family life and the like, and the mental depression and physical and mental health of patients are greatly influenced. 3. Cognitive impairment is mainly manifested by memory impairment, mental decline, character change, etc., and eventually gradually loses working ability and even living ability.
Seizures are characterized by several points: 1. grand onset: accounting for about 50% of epileptic seizures, most commonly between the ages of 1 year or 14-17 years. A grand episode can be divided into four periods: (1) and (3) a premonitory stage: dizziness and stomach discomfort. (2) A strong straight period: sudden loss of consciousness, falling over the ground, bending back the head and strengthening the limbs, the patient sends out lambs-like roar, bluish purple face, mydriasis and apnea due to the spasm of the diaphragm, lasting for tens of seconds, and the like. (3) Clonic phase: the muscles of the whole body have rhythmic twitching, tongue biting and white foam spitting in the mouth, which can be accompanied by incontinence of urine and feces, and generally lasts for 1-3 minutes. (4) A recovery period: generally, the patient can be awake for tens of minutes, and the patient cannot remember about the attack process, and is full of pain and hypodynamia. The individual patients have the conditions of mania, running and screaming, and people and objects being destroyed in the recovery period. 2. Small attack: the seizures of epilepsy are also called absence seizures, and are typically characterized by transient loss of consciousness, complete loss of most consciousness, occasional slight disturbance of consciousness, understanding the surroundings, and being able to hear the question but not answer. The disturbance of consciousness is characterized by its short-term and frequent occurrence. Most of the medicine has 2-15 seconds per attack, no more than 1 minute, and several times to tens of times per day. Occurs suddenly and terminates suddenly. It is manifested as sudden speech and activity interruption, fixation of both eyes, occasional upturning, sometimes pale complexion, and no aura. When the rice bowl is broken, the original activities are continued after the rice bowl is stopped. 3. Psychomotor seizures: on the background of the cognitive disorder, there are usually illusions, hallucinations, and automatism. It is also called temporal lobe epilepsy because it is usually caused by temporal lobe pathological changes. The onset age is late in various types of epilepsy and the onset is usually first in about 20 years old. About 40% of patients develop premonitory symptoms, such as upset stomach, auditory hallucinations, bad taste, vertigo, nausea, fear, etc.
The current treatment of epilepsy includes drug therapy, surgical therapy, neuromodulation therapy, and the like.
At present, the treatment of epilepsy at home and abroad mainly takes drug therapy as main treatment. After regular antiepileptic drug treatment, seizures of about 70% of patients can be controlled, wherein 50% -60% of patients can be cured after 2-5 years of treatment, and the patients can work and live as normal people. Therefore, rational and regular anti-epileptic medication is critical.
General principles when selecting antiepileptic drugs: the correct classification of seizures and epileptic syndromes is the basis for rational drug selection. In addition, factors such as the age (children, adults, and the elderly), sex, concomitant diseases, and the potential side effects of antiepileptic drugs on the future quality of life of the patient are also considered. If the infant patient can not swallow the tablet, the syrup preparation is not only beneficial to the infant patient to take, but also convenient to control the dosage. When selecting the medicine, the children patients should pay attention to select the medicine which has no influence on cognitive function, memory and attention as much as possible. The elderly suffer from a plurality of diseases together, have a plurality of medicines combined, have a plurality of interactions among the medicines, and are more sensitive to anti-epileptic medicines and have more prominent side effects. Therefore, when selecting antiepileptic drugs for the elderly epileptic patients, the side effects of the drugs and the interaction between the drugs must be considered. For patients with epilepsy in women of childbearing age, attention should be paid to the effects of antiepileptic drugs on hormones, libido, female characteristics, pregnancy, fertility and teratogenicity. Although traditional antiepileptic drugs (such as phenytoin sodium and phenobarbital) have certain clinical efficacy, the traditional antiepileptic drugs have more side effects, such as gingival hyperplasia, hair increase, high teratogenesis rate, hyperactivity, inattention and the like, and are not easy to tolerate by patients.
Diazepam is a benzodiazepine anxiolytic having anxiolytic, sedative, hypnotic, anticonvulsant, antiepileptic, and central muscle relaxant effects. Is the most common hypnotic in clinic at present. In addition, the compound preparation has a good anti-epileptic effect, is very effective to the status epilepticus, can control 70 to 80 percent of epilepsy in intravenous injection, and is required to be injected intravenously in the process of controlling the status epilepticus.
Disclosure of Invention
The invention provides a diazepam nasal spray which is used for treating recurrent seizures of epilepsy. The nasal cavity mucosa administration has the characteristics of quick response, complete drug absorption, no influence from gastrointestinal tract first-pass effect and convenient administration, compared with the injection, the nasal cavity spray is provided with a special container, does not need complex operation before use, is quick and simple to use, and is particularly suitable for repeated attack of epilepsy. Because the epileptic seizure has acute onset, long course of disease and easy repetition, and the long-term hospitalization and the repeated emergency delivery are not feasible, the timely administration of the quick and effective medicament under the condition of the repeated seizures is very important. The diazepam nasal spray provided by the invention is convenient to administer, does not need professional medical knowledge, can be operated according to instructions, is quick in effect taking after nasal administration, is not influenced by body rigidity and muscle tension during epileptic seizure, and has better administration operation compared with an injection.
The invention provides a diazepam nasal spray which is characterized by comprising diazepam, a solvent, a penetration enhancer, an antioxidant and a bacteriostatic agent.
The solvent of the nasal spray can use alcohol or purified water or the combination of the alcohol and the purified water, the solvent selected by the invention is 75% ethanol, and the 75% ethanol has good mucosal penetrability and can promote the rapid absorption of the medicine under the condition of ensuring the solubility of the medicine.
The nasal spray is a liquid preparation, and generally needs to be added with a bacteriostatic agent, wherein the bacteriostatic agent selected by the invention is benzyl alcohol with the concentration of 5% (V/V) to 15% (V/V), and preferably 10%. In addition, benzyl alcohol also has local anesthetic effect, and can relieve irritation of high concentration ethanol to nasal mucosa.
In order to promote the rapid absorption of the medicine, the nasal spray provided by the invention is added with a penetration enhancer, wherein the penetration enhancer is lauroyl maltoside, and the content of the penetration enhancer is 0.1-2.0%, preferably 1%.
In order to enhance the stability of the medicine, the antioxidant is added into the nasal spray, the antioxidant is vitamin E, and the content of the antioxidant is 10mg/ml to 100mg/ml, preferably 50 mg/ml.
The preparation method of the nasal spray provided by the invention comprises the following steps: taking 75% ethanol, sequentially adding benzyl alcohol and vitamin E, stirring for dissolving, then adding lauroyl maltoside, stirring for dissolving, finally adding diazepam, stirring for dissolving, sterilizing, filtering to obtain clear solution, and filling into a bottle special for nasal spray.
Detailed Description
The invention is described below by way of non-limiting examples.
Example one
| Composition (I) | Dosage of |
| Diazepam | 25g |
| Lauroyl maltoside | 10g |
| Benzyl alcohol | 100ml |
| Vitamin E | 50g |
| 75% ethanol | Adding to 1000ml |
| Total amount of | 1000ml |
The preparation method comprises the following steps: dissolving lauroyl maltoside, vitamin E and benzyl alcohol in anhydrous alcohol, stirring, adding diazepam, stirring, filtering with 0.22 μm filter membrane for sterilization, and bottling into quantitative nasal spray bottle with 10ml per bottle and 0.1ml per press for administration.
Example two
The preparation method comprises the following steps: dissolving lauroyl maltoside, vitamin E and benzyl alcohol in anhydrous alcohol, stirring, adding diazepam, stirring, filtering with 0.22 μm filter membrane for sterilization, and bottling into quantitative nasal spray bottle with 10ml per bottle and 0.1ml per press for administration.
EXAMPLE III
| Composition (I) | Dosage of |
| Diazepam | 100g |
| Lauroyl maltoside | 10g |
| Benzyl alcohol | 150ml |
| Vitamin E | 100g |
| 75% ethanol | Adding to 1000ml |
| Total amount of | 1000ml |
The preparation method comprises the following steps: dissolving lauroyl maltoside, vitamin E and benzyl alcohol in anhydrous alcohol, stirring, adding diazepam, stirring, filtering with 0.22 μm filter membrane for sterilization, and bottling into quantitative nasal spray bottle with 10ml per bottle and 0.1ml per press for administration.
Example four
| Composition (I) | Dosage of |
| Diazepam | 50g |
| Lauroyl radicalMaltoside | 1g |
| Benzyl alcohol | 50ml |
| Vitamin E | 10g |
| 75% ethanol | Adding to 1000ml |
| Total amount of | 1000ml |
The preparation method comprises the following steps: dissolving lauroyl maltoside, vitamin E and benzyl alcohol in 75% ethanol, stirring, adding diazepam, stirring, filtering with 0.22 μm filter membrane for sterilization, and bottling into quantitative nasal spray bottle with 10ml each bottle and 0.1ml each bottle for administration.
Comparative examples
| Composition (I) | Dosage of |
| Diazepam | 100g |
| Benzyl alcohol | 150ml |
| Vitamin E | 100g |
| 75% ethanol | Adding to 1000ml |
| Total amount of | 1000ml |
The preparation method comprises the following steps: dissolving vitamin E and benzyl alcohol in 75% ethanol, stirring, adding diazepam, stirring, filtering with 0.22 μm filter membrane for sterilization, and bottling into quantitative nasal spray bottle with volume of 10ml each and 0.1ml each for administration.
Nasal mucosa permeability test
The pig nose which is dead within 1 hour is taken down by the treatment of nasal mucosa for experiment, the nasal cavity is cut, the nasal septum and the turbinates at two sides are exposed, the nasal cavity film is carefully stripped by a round-head thin glass rod and tweezers, the residual bloodstain on the film is washed away by normal saline, and then the film is put on a piece of aluminum foil and spread for immediate use.
The effective diffusion area is 3.14cm by Franz diffusion cell method2The receiving tank volume was 14 mL. An electromagnetic stirrer and 14mL of normal saline are added into the receiving chamber, and air bubbles are discharged in time. Fixing the mucous membrane layer of pig nose between the receiving chamber and the supplying chamber, placing on a constant temperature magnetic stirrer with water bath temperature of 37 deg.C and 3000r/min, and balancing for 20 min. Then, 1mL of the diazepam nasal spray in example 3 and the comparative example is added to nasal mucosa of a supply room, 1mL of the diazepam nasal spray is sampled at 0min, 5 min, 10 min, 15 min, 20min and 30min respectively, and an equal amount of fresh receiving solution is supplemented after each sampling, so that 6 samples are taken in total. After the obtained sample was filtered through a 0.22 μm filter membrane, 20 μ L of the sample was injected into a liquid chromatograph to measure the peak area, and the amount thereof was calculated. Octadecylsilane chemically bonded silica is used as a filling agent; flowing methanol-water (70: 30); the detection wavelength was 254 nm. The cumulative permeation amount (Qn) is calculated.
Cn and Ci represent the mass concentration of drug (g/mL) measured at the n-th and i-th sampling points, respectively, and V0 represent the volume of the receiving cell and the sampling volume (mL), respectively.
As a result:
| time of day | 5min | 10min | 15min | 20min | 30min |
| Example 3 | 71.2％ | 88.5％ | 92.6％ | 99.3％ | 99.5％ |
| Comparative examples | 46.8％ | 58.3％ | 69.8％ | 78.4％ | 85.2％ |
According to the results, the nasal mucosa permeation rate of the sample of example 3 is significantly higher than that of the comparative example, indicating that the penetration enhancer lauroyl maltoside plays a significant role in the permeation of diazepam.
Results of stability test of the formulation of the invention (example 3)
Claims (9)
1. A nasal spray containing diazepam is characterized by comprising diazepam, a solvent, a penetration enhancer, an antioxidant and a bacteriostatic agent.
2. A nasal spray as claimed in claim 1 wherein the diazepam is present in an amount of from 2.5% to 10% (W/V).
3. The nasal spray according to claim 1, wherein the solvent is 75% ethanol.
4. The nasal spray according to claim 1, wherein the antioxidant is vitamin E.
5. The nasal spray of claim 1, wherein the bacteriostatic agent is benzyl alcohol.
6. A nasal spray according to claim 5, wherein the concentration of benzyl alcohol is 5% to 15% (V/V), preferably 10%.
7. A nasal spray according to claim 4, wherein the vitamin E content is 1% to 10% (W/V), preferably 5% (W/V).
8. The nasal spray according to claim 1, wherein the penetration enhancer is lauroyl maltoside.
9. A nasal spray according to claim 8, wherein the lauroyl maltoside is present in an amount of 0.1% to 2.0% (W/V), preferably 1% (W/V).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010303079.0A CN111529489A (en) | 2020-04-17 | 2020-04-17 | Nasal spray containing diazepam |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010303079.0A CN111529489A (en) | 2020-04-17 | 2020-04-17 | Nasal spray containing diazepam |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN111529489A true CN111529489A (en) | 2020-08-14 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010303079.0A Pending CN111529489A (en) | 2020-04-17 | 2020-04-17 | Nasal spray containing diazepam |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111529489A (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2271347A4 (en) * | 2008-03-28 | 2013-07-03 | Hale Biopharma Ventures Llc | Administration of benzodiazepine compositions |
| CN103619338A (en) * | 2011-03-31 | 2014-03-05 | 阿索尔达治疗有限公司 | Intranasal benzodiazepine pharmaceutical compositions |
| CN103796656A (en) * | 2011-06-14 | 2014-05-14 | 哈尔生物药投资有限责任公司 | Administration of benzodiazepine |
| CN110996912A (en) * | 2017-08-20 | 2020-04-10 | 福摩莱克斯医药创新有限公司 | Dry powder compositions for intranasal delivery |
-
2020
- 2020-04-17 CN CN202010303079.0A patent/CN111529489A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2271347A4 (en) * | 2008-03-28 | 2013-07-03 | Hale Biopharma Ventures Llc | Administration of benzodiazepine compositions |
| CN103619338A (en) * | 2011-03-31 | 2014-03-05 | 阿索尔达治疗有限公司 | Intranasal benzodiazepine pharmaceutical compositions |
| CN103796656A (en) * | 2011-06-14 | 2014-05-14 | 哈尔生物药投资有限责任公司 | Administration of benzodiazepine |
| CN107737100A (en) * | 2011-06-14 | 2018-02-27 | 哈尔生物药投资有限责任公司 | The administration of Benzodiazepine composition |
| CN110996912A (en) * | 2017-08-20 | 2020-04-10 | 福摩莱克斯医药创新有限公司 | Dry powder compositions for intranasal delivery |
Non-Patent Citations (1)
| Title |
|---|
| 吴小林等主编: "《药物化学》", 31 August 2018 * |
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Application publication date: 20200814 |