阅读说明：本技术 一种药物组合物及其制备方法和用途 (Pharmaceutical composition and preparation method and application thereof ) 是由 杨洁 吴有斌 曲龙妹 田峦鸢 汪淼 吕金良 杨玉萍 张丽娜 李莉娥 李仕群 杜文 于 2018-09-12 设计创作，主要内容包括：本申请公开了一种药物组合物,其包括镇静药和麻醉药。该药物组合物适用于消化道内镜诊疗的程序化控释给药制剂,可以是一种含有镇静药和麻醉药的鼻用微球制剂,镇静药速释先起效,可先缓解患者紧张、焦虑和恐惧情绪,麻醉药包裹在微球中随后起效,可维持麻醉以便于检查的进行。该制剂既增加了患者的顺应性,而且给药更方便快捷,节约诊断时间,提高诊疗效率。(A pharmaceutical composition comprising a sedative and an anesthetic is disclosed. The pharmaceutical composition is suitable for programmed controlled release administration preparation for alimentary tract endoscope diagnosis and treatment, and can be a nasal microsphere preparation containing sedative and anesthetic, wherein the sedative can be released first to take effect, and can relieve the stress, anxiety and fear of patients, and the anesthetic is wrapped in the microsphere to take effect later, so that the anesthesia can be maintained to facilitate the examination. The preparation not only increases the compliance of patients, but also has the advantages of more convenient and faster administration, saves the diagnosis time and improves the diagnosis and treatment efficiency.)

1. A pharmaceutical composition comprising a sedative and an anesthetic.

2. The pharmaceutical composition of claim 1, wherein said sedative is selected from the group consisting of: a compound of formula (I), diazepam, midazolam, alprazolam and dexmedetomidine, or a pharmaceutically acceptable salt thereof;

r in the formula (I)₁Is hydrogen, methyl, ethyl, or isopropyl, R₂Is methyl or ethyl.

3. The pharmaceutical composition of claim 1, wherein the anesthetic is selected from the group consisting of: meperidine, ketamine, dexketamine, fentanyl, remifentanil, alfentanil, sufentanil, etomidate, propofol, and fospropofol sodium, or a pharmaceutically acceptable salt thereof.

4. The pharmaceutical composition according to claim 1, wherein the mass ratio of the sedative drug to the anesthetic in the composition is 1: 1-1: 48.

5. The pharmaceutical composition of claim 2, wherein the pharmaceutically acceptable salt is a hydrochloride, maleate, besylate, tosylate, or esylate.

6. The pharmaceutical composition of claim 3, wherein the pharmaceutically acceptable salt is a hydrochloride salt, or a citrate salt.

7. The pharmaceutical composition of any one of claims 1-6, wherein the anesthetic is combined with a pharmaceutical carrier to form anesthetic microspheres, which are then mixed with the sedative.

8. The pharmaceutical composition of claim 7, wherein the pharmaceutical composition is administered nasally, or nasally.

9. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition further comprises a cross-linking agent, a suspending agent, a solubilizing agent, a pharmaceutical carrier, and an osmotic pressure regulating agent.

10. The pharmaceutical composition according to claim 9, wherein the cross-linking agent is selected from one or more of glutaraldehyde, formaldehyde, and a saturated chloroform solution of phthalide chloride;

optionally, the suspending agent is one or more selected from glycerol, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl cellulose, carbopol, and povidone;

optionally, the solubilizer is selected from one or more of tween 20, tween 80 and Kolliphor HS 15;

optionally, the carrier is selected from one or more of starch, chitosan, gelatin and carbomer;

optionally, the osmotic pressure regulator is sodium chloride.

11. A process for the preparation of a pharmaceutical composition according to claim 9, comprising the steps of:

A. dissolving an anesthetic in a drug carrier solution to obtain a water phase;

B. slowly adding the water phase into the oil phase by a syringe under electric stirring, and emulsifying at high speed to obtain W/O emulsion;

C. slowly adding a cross-linking agent, curing, and standing until no bubbles exist;

D. spray drying at the inlet temperature, the air flow rate and the outlet temperature by using a spray dryer to obtain anesthetic microspheres;

E. resuspending the anesthetic microspheres with a sedative solution, and filling into a dropping bottle.

12. The method for preparing a pharmaceutical composition according to claim 11, wherein the concentration of the pharmaceutical carrier solution in step a is 1-5%;

optionally, the volume ratio of the water phase to the oil phase in the step B is 1: 2-1: 10;

optionally, the dosage of the cross-linking agent in the step C is 1-100 ml;

optionally, the sedative solution in the step E is an aqueous solution, and the concentration of the sedative solution is 0.1 mg/ml-8 mg/ml;

optionally, the sedative solution of the step E also contains a suspending agent or a solubilizer, and the proportion of the thickener or the solubilizer in the sedative solution is not more than 5 percent;

optionally, the sedative solution of the step E also contains an osmotic pressure regulator, and the osmotic pressure regulator is 0.7-0.9% of sodium chloride solution.

13. Use of the pharmaceutical composition according to any one of claims 1 to 10 in gastrointestinal endoscopy.

Technical Field

The application belongs to the technical field of medicines, and particularly relates to a pharmaceutical composition which comprises a sedative and an anesthetic; in particular, the pharmaceutical composition can be used for digestive tract endoscope diagnosis and treatment.

Background

The digestive tract endoscope diagnosis and treatment technology comprises gastroscope, colonoscope, enteroscope, retrograde cholangiopancreatography, endoscopic mucosal resection, endoscopic submucosal dissection and the like, and is the most common and reliable diagnosis and treatment method for digestive tract diseases. However, most patients feel nervous, anxious and frightened mind in the operation of the digestive endoscopy, and cough, nausea, vomiting, increased heart rate, increased blood pressure, arrhythmia and the like are easy to occur in the examination process, and even serious complications such as angina, myocardial infarction, stroke or sudden cardiac arrest and the like are induced. A small proportion of patients cannot tolerate and cooperate to complete a digestive endoscopy procedure, so that an endoscopist cannot clearly diagnose and treat related diseases.

At present, the sedative clinically used for the endoscope of the digestive tract is mainly benzodiazepine

Narcotics clinically used in gastrointestinal endoscopy are classified into intravenous and inhalational narcotics, the inhalational narcotics being volatile liquids or gases such as sevoflurane, nitric oxide, etc. intravenous narcotics include opioids (such as pethidine, fentanyl, remifentanil, sufentanil), imidazoles (such as etomidate), phencyclidine (such as ketamine) and non-barbiturates (such as propofol) (gastroenterology, 2010, 15 (10)). the sedatives and narcotics are mostly administered intravenously, particularly for some drugs such as propofol which cause pain at the injection site (journal of chinese utility, 2010,30(7)), further aggravate the psychology of stress, anxiety and fear in patients, are not co-administered, especially in young patients, thus delaying diagnosis.

Disclosure of Invention

The inventor develops a pharmaceutical composition which comprises a sedative and an anesthetic, and when the pharmaceutical composition is used for gastrointestinal endoscopy diagnosis and treatment, the sedative can take effect firstly, relieve the tension, anxiety and fear of patients, and the anesthetic takes effect later and can maintain anesthesia, so that the compliance of the patients is improved, the administration is more convenient and faster, the diagnosis time is saved, and the diagnosis and treatment efficiency is improved.

It is an object of the present application to provide a pharmaceutical composition comprising a sedative and an anesthetic.

Another object of the present application is to provide a process for the preparation of the above pharmaceutical composition.

A third object of the present application is to provide the use of the above pharmaceutical composition.

In particular, in embodiments herein, the present application provides a pharmaceutical composition comprising a sedative and an anesthetic.

In some embodiments of the present application, there is provided a pharmaceutical composition comprising a sedative and an anesthetic; wherein the sedative is selected from the group consisting of: a compound of formula (I), diazepam, midazolam, alprazolam and dexmedetomidine, or a pharmaceutically acceptable salt thereof;

r in the formula (I)₁Is hydrogen, methyl, ethyl, or isopropyl, R₂Is methyl or ethyl.

In other embodiments of the present application, the present application provides a pharmaceutical composition comprising a sedative and an anesthetic; wherein the anesthetic is selected from the group consisting of: meperidine, ketamine, dexketamine, fentanyl, alfentanil, sufentanil, etomidate, propofol, and fospropofol sodium, or a pharmaceutically acceptable salt thereof.

In some embodiments of the present application, there is provided a pharmaceutical composition comprising a sedative and an anesthetic; wherein the sedative is selected from the group consisting of: a compound of formula (I), diazepam, midazolam, alprazolam and dexmedetomidine, or a pharmaceutically acceptable salt thereof;

r in the formula (I)₁Is hydrogen, methyl, ethyl, or isopropyl, R₂Is methyl or ethyl;

the anesthetic is selected from the group consisting of: meperidine, ketamine, dexketamine, fentanyl, remifentanil, alfentanil, sufentanil, etomidate, propofol, and fospropofol sodium, or a pharmaceutically acceptable salt thereof.

In an embodiment of the present application, there is provided a pharmaceutical composition, wherein the mass ratio of the sedative to the anesthetic is 1: 1-1: 48.

In an embodiment of the present application, there is provided a pharmaceutical composition wherein the pharmaceutically acceptable salt in the sedative drug can be, but is not limited to, hydrochloride, maleate, besylate, tosylate, or esylate.

In an embodiment of the present application, a pharmaceutical composition is provided, wherein the pharmaceutically acceptable salt in the anesthetic described herein may be, but is not limited to, hydrochloride, or citrate.

In an exemplary embodiment of the present application, there is provided a pharmaceutical composition comprising a sedative and an anesthetic; wherein the sedative is selected from a compound shown as a formula (I) or a pharmaceutically acceptable salt thereof:

r in the formula (I)₁Is hydrogen, methyl, ethyl, or isopropyl, R₂Is methyl or ethyl;

the anesthetic is selected from the group consisting of: meperidine, ketamine, dexketamine, fentanyl, remifentanil, alfentanil, sufentanil, etomidate, propofol, and fospropofol sodium, or a pharmaceutically acceptable salt thereof.

In an exemplary embodiment of the present application, there is provided a pharmaceutical composition comprising a sedative and an anesthetic; wherein the sedative is selected from a compound shown as a formula (I) or a pharmaceutically acceptable salt thereof:

r in the formula (I)₁Is hydrogen, R₂Is methyl; or, R₁Is hydrogen, R₂Is ethyl; or, R₁Is methyl, R₂Is methyl; or, R₁Is methyl, R₂Is ethyl; or, R₁Is ethyl, R₂Is methyl; or, R₁Is ethyl, R₂Is ethyl; or, R₁Is isopropyl, R₂Is methyl; or, R₁Is isopropyl, R₂Is ethyl.

In some exemplary embodiments of the present application, there is provided a pharmaceutical composition comprising a sedative and an anesthetic; wherein the sedative is selected from a compound shown as a formula (I) or a pharmaceutically acceptable salt thereof:

r in the formula (I)₁Is hydrogen, methyl, ethyl, or isopropyl, R₂Is methyl or ethyl; preferably, R₁Is methyl, R₂Is methyl; or R₁Is isopropyl, R₂Is ethyl;

the anesthetic is alfentanil or pharmaceutically acceptable salt thereof.

In some exemplary embodiments of the present application, there is provided a pharmaceutical composition comprising a sedative and an anesthetic; wherein the sedative is selected from a compound shown as a formula (I) or a pharmaceutically acceptable salt thereof:

r in the formula (I)₁Is hydrogen, methyl, ethyl, or isopropyl, R₂Is methyl or ethyl; preferably, R₁Is methyl, R₂Is methyl;

the anesthetic is fentanyl or pharmaceutically acceptable salt thereof.

In some exemplary embodiments of the present application, there is provided a pharmaceutical composition comprising a sedative and an anesthetic; wherein the sedative is selected from a compound shown as a formula (I) or a pharmaceutically acceptable salt thereof:

r in the formula (I)₁Is hydrogen, methyl, ethyl, or isopropyl, R₂Is methyl or ethyl;

the anesthetic is dexketamine or a pharmaceutically acceptable salt thereof.

In an exemplary embodiment of the present application, there is provided a pharmaceutical composition comprising a sedative and an anesthetic; wherein the sedative is dexmedetomidine or pharmaceutically acceptable salt thereof; the anesthetic is dexketamine or a pharmaceutically acceptable salt thereof.

In an exemplary embodiment of the present application, there is provided a pharmaceutical composition comprising a sedative and an anesthetic; wherein the sedative is dexmedetomidine or pharmaceutically acceptable salt thereof; the anesthetic is fospropofol disodium or pharmaceutically acceptable salts thereof.

In an exemplary embodiment of the present application, there is provided a pharmaceutical composition comprising a sedative and an anesthetic; wherein the sedative is dexmedetomidine or pharmaceutically acceptable salt thereof; the anesthetic is remifentanil or a pharmaceutically acceptable salt thereof.

In an exemplary embodiment of the present application, there is provided a pharmaceutical composition comprising a sedative and an anesthetic; wherein the sedative is midazolam or pharmaceutically acceptable salt thereof; the anesthetic is alfentanil or pharmaceutically acceptable salt thereof.

In an exemplary embodiment of the present application, there is provided a pharmaceutical composition comprising a sedative and an anesthetic; wherein the sedative is alprazolam or pharmaceutically acceptable salt thereof; the anesthetic is dexketamine or a pharmaceutically acceptable salt thereof.

In an exemplary embodiment of the present application, there is provided a pharmaceutical composition comprising a sedative and an anesthetic; wherein the sedative is diazepam or a pharmaceutically acceptable salt thereof; the anesthetic is dexketamine or a pharmaceutically acceptable salt thereof.

In an exemplary embodiment of the present application, there is provided a pharmaceutical composition comprising a sedative and an anesthetic; wherein the sedative is midazolam or pharmaceutically acceptable salt thereof; the anesthetic is sufentanil or a pharmaceutically acceptable salt thereof.

In embodiments herein, the present application provides a pharmaceutical composition comprising a sedative and an anesthetic; wherein the anesthetic and the drug carrier form anesthetic microspheres, which are then mixed with a sedative.

In embodiments herein, the present application provides a pharmaceutical composition comprising a sedative and an anesthetic; wherein, the drug carrier in the anesthetic microspheres is selected from one or more of starch, chitosan, gelatin and carbomer.

In embodiments herein, the present application provides a pharmaceutical composition comprising a sedative and an anesthetic; the composition also comprises other auxiliary materials, wherein the other auxiliary materials are selected from one or more of a cross-linking agent, a suspending agent, a solubilizer and an osmotic pressure regulator.

In embodiments herein, there is provided a pharmaceutical composition comprising a sedative and an anesthetic, together with other excipients selected from one or more of a cross-linking agent, a suspending agent, a solubilizing agent, and an osmotic pressure regulator; wherein, the cross-linking agent is selected from one or more of glutaraldehyde, formaldehyde and saturated chloroform solution of phthalein chloride.

In embodiments herein, there is provided a pharmaceutical composition comprising a sedative and an anesthetic, together with other excipients selected from one or more of a cross-linking agent, a suspending agent, a solubilizing agent, and an osmotic pressure regulator; wherein, the suspending agent is selected from one or more of glycerol, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl cellulose, carbopol and povidone.

In embodiments herein, there is provided a pharmaceutical composition comprising a sedative and an anesthetic, together with other excipients selected from one or more of a cross-linking agent, a suspending agent, a solubilizing agent, and an osmotic pressure regulator; wherein, the solubilizer is selected from one or more of Tween 20, Tween 80 and KolliphorHS 15.

In embodiments herein, there is provided a pharmaceutical composition comprising a sedative and an anesthetic, together with other excipients selected from one or more of a cross-linking agent, a suspending agent, a solubilizing agent, and an osmotic pressure regulator; wherein, the osmotic pressure regulator is sodium chloride.

In embodiments herein, the present application provides a pharmaceutical composition comprising a sedative and an anesthetic; wherein, the medicine composition is used for nasal administration or nasal administration.

In embodiments herein, the present application provides a pharmaceutical composition comprising a sedative and an anesthetic; the medicine composition is used for nasal administration during alimentary tract endoscopic diagnosis and treatment or nasal administration during alimentary tract endoscopic diagnosis and treatment.

In some embodiments of the present application, there is provided a pharmaceutical composition comprising a sedative and an anesthetic; wherein, the pharmaceutical composition is optionally administered nasally, or nasally; wherein, the anesthetic and the drug carrier form anesthetic microspheres, and then the anesthetic microspheres are mixed with the sedative;

the sedative is selected from the group consisting of: compounds of formula (I), diazepam, midazolam, alprazolam and dexmedetomidine, or a pharmaceutically acceptable salt thereof,

r in the formula (I)₁Is hydrogen, methyl, ethyl, or isopropyl, R₂Is methyl or ethyl;

the anesthetic is selected from the group consisting of: meperidine, ketamine, dexketamine, fentanyl, remifentanil, alfentanil, sufentanil, etomidate, propofol, and fospropofol sodium, or a pharmaceutically acceptable salt thereof;

optionally, the mass ratio of the sedative to the anesthetic is 1: 1-1: 48.

In another aspect, the present application provides a method for preparing a pharmaceutical composition of a sedative and an anesthetic as described above, comprising the steps of:

A. dissolving an anesthetic in a drug carrier solution to obtain a water phase;

B. slowly adding the water phase obtained in the step A into the oil phase through an injector under the condition of electric stirring, and emulsifying at a high speed to prepare a W/O type emulsion;

C. slowly adding a cross-linking agent, curing, and standing until no bubbles exist;

D. spray drying at the inlet temperature, the air flow rate and the outlet temperature by using a spray dryer to obtain anesthetic microspheres;

E. resuspending the anesthetic microspheres with a sedative solution, and filling into a dropping bottle.

The application provides a preparation method of the pharmaceutical composition, wherein the mass volume percentage concentration of the drug carrier in the drug carrier aqueous solution in the step A is 1-5% (g/100 ml).

The preparation method of the pharmaceutical composition provided by the application comprises the step B, wherein the volume ratio of the water phase to the oil phase in the step B is 1: 2-1: 10.

According to the preparation method of the pharmaceutical composition provided by the application, the dosage of the cross-linking agent in the step C is 1-100 ml according to the condition of a pharmaceutical carrier.

In the preparation method of the pharmaceutical composition provided by the application, the sedative solution in the step E is an aqueous solution, and the concentration of the sedative solution is 0.1 mg/ml-8 mg/ml.

The preparation method of the pharmaceutical composition provided by the application, wherein the sedative solution in the step E also contains a suspending agent or a solubilizer, and the thickening agent or the solubilizer accounts for no more than 5% of the sedative solution by mass and volume (g/100 ml).

In the preparation method of the pharmaceutical composition provided by the application, the sedative solution in the step E further contains 0.7-0.9% by mass/volume (g/100ml) of sodium chloride as an osmotic pressure regulator.

In a third aspect, the invention provides an application of the pharmaceutical composition in digestive tract endoscope diagnosis and treatment medicines. The pharmaceutical composition can be converted according to the weight of a patient and then dropped into the nose when the gastrointestinal endoscope diagnosis and treatment is carried out. When the nasal drop is used, the patient is in the supine vertical position: the patient lies on the bed with his back, the shoulder is padded with a pillow, and the head is tilted backwards to make the nostril face upward, and the connecting line of the nostril and forehead is perpendicular to the operation table surface. The liquid medicine is dripped into each nostril at each side for about 1min, and then the patient sits up and lowers the head, so that the redundant liquid medicine flows to the bottom of the nose from the top of the nasal cavity, and the liquid medicine can be uniformly distributed on the surface of the nasal mucosa, thereby ensuring that the liquid medicine is absorbed to the maximum extent. The medicine can also be administered through nose by using a mucous Membrane Atomizing Device (MAD), and the medicine can be uniformly dispersed into smaller drops which are easier to adsorb on the nasal mucous membrane, so that the medicine can be absorbed to the maximum extent.

Compared with the prior art, the application has the following advantages and positive effects:

(1) through a large amount of researches, the inventor finds that the pharmaceutical composition has good stability and can still keep stable after being stored for 12 months for a long time;

(2) the quick-release sedative preparation prepared by the application takes effect firstly, can relieve the tension, anxiety and fear of a patient firstly, and the anaesthetic is wrapped in the microsphere to take effect later and can maintain the anaesthetic so as to facilitate the examination, so that the compliance of the patient is increased, the administration is more convenient and faster, the diagnosis time is saved, and the diagnosis and treatment efficiency is improved;

(3) the application adopts the material with low toxicity and good adhesiveness to the cilia of the nasal cavity, and the prepared nasal microspheres do not influence the movement of the cilia of the nose, have no obvious irritation to the nasal mucosa and have good safety;

(4) the bioavailability of the pharmaceutical composition reaches over 90 percent, and is basically close to that of the pharmaceutical composition administered by a micro pump or an injection;

additional features and advantages of the application will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by the practice of the application. The objectives and other advantages of the application may be realized and attained by the structure particularly pointed out in the written description and claims hereof as well as the appended drawings.

Drawings

The accompanying drawings are included to provide a further understanding of the claimed subject matter and are incorporated in and constitute a part of this specification, illustrate embodiments of the subject matter and together with the description serve to explain the principles of the subject matter and not to limit the subject matter.

FIG. 1 is a schematic representation of the structure of a nasal microsphere formulation containing a sedative and anesthetic in accordance with the present application;

FIG. 2 shows example 1 of the present application containing a sedative agent (formula (I), R)₁＝CH₃，R₂＝CH₃Besylate) and alfentanil hydrochloride;

FIG. 3 shows example 1 of the present application containing a sedative agent (formula (I), R)₁＝CH₃，R₂＝CH₃Besylate) and alfentanil hydrochloride in vitro accumulation drug release profile;

FIG. 4 is the results of an in vivo pharmacokinetic study of the microsphere formulation combination prepared in example 1;

FIG. 5 is the results of an in vivo pharmacokinetic study of the microsphere formulation combination prepared in example 2;

FIG. 6 is the results of an in vivo pharmacokinetic study of the microsphere formulation combination prepared in example 3;

FIG. 7 is the results of an in vivo pharmacokinetic study of the microsphere formulation combination prepared in example 4;

FIG. 8 is the results of an in vivo pharmacokinetic study of the microsphere formulation combination prepared in example 5;

FIG. 9 is the results of an in vivo pharmacokinetic study of the microsphere formulation combination prepared in example 6;

FIG. 10 is the results of an in vivo pharmacokinetic study of the microsphere formulation combination prepared in example 7;

FIG. 11 is the results of an in vivo pharmacokinetic study of the microsphere formulation combination prepared in example 8;

FIG. 12 is the results of an in vivo pharmacokinetic study of the microsphere formulation combination prepared in example 9;

FIG. 13 is the results of an in vivo pharmacokinetic study of the microsphere formulation combination prepared in example 10.

Detailed Description

To make the objects, technical solutions and advantages of the present application more apparent, embodiments of the present application will be described in detail below with reference to the accompanying drawings. It should be noted that the embodiments and features of the embodiments in the present application may be arbitrarily combined with each other without conflict.

The following examples are given solely for the purpose of illustration and are not intended to be construed as limitations of the present application, as many variations thereof are possible without departing from the spirit and scope of the application.

The instrument comprises the following steps:

ULTRA-TURRAX disperser, L-117 small-sized spray dryer for laboratory, OMEC laser particle size analyzer, American DAI high performance liquid chromatograph, JJ-1 timing electric stirrer, YS100 optical microscope, JEM-6700F cold field emission scanning electron microscope, and SHZ-B constant temperature water bath oscillator