CN110801515A - Insulin oral spray and preparation process method thereof - Google Patents

Insulin oral spray and preparation process method thereof Download PDF

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Publication number
CN110801515A
CN110801515A CN201911007945.5A CN201911007945A CN110801515A CN 110801515 A CN110801515 A CN 110801515A CN 201911007945 A CN201911007945 A CN 201911007945A CN 110801515 A CN110801515 A CN 110801515A
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insulin
stirring
shearing
oral spray
solution
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王晶
徐辉碧
杨继林
陈新
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
    • 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
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • 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
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • 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
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Abstract

The invention discloses a process for preparing insulin oral spray, which comprises insulin, promoter, cosolvent, flavoring agent, bacteriostat and buffer solution, wherein each 1000ml oral spray comprises: insulin 10,000U-80,000U; 15-45 g of soybean lecithin as an accelerant; 50-120g of propylene glycol and 5-15 ml of ethanol as cosolvent; 1-5 g of borneol as a flavoring agent; 1-4 g of phenol as a bacteriostatic agent; the pH of the buffer solution was 6.8 to 7.8. The invention improves the component formula and the preparation process of the insulin oral spray, improves the preparation quality of the medicament, shortens the production period, and can provide safer and simpler administration modes and medicaments for patients with diabetes.

Description

Insulin oral spray and preparation process method thereof
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a preparation process method of an insulin oral spray, in particular to a formula and a preparation method for preparing insulin such as insulin oral spray.
Background
Insulin is produced by including recombinant human insulin, animal insulin, and insulin analogs known in the art; taking recombinant human insulin as an example, the recombinant human insulin is very easy to be degraded by gastric acid and various digestive enzymes in gastrointestinal tracts, can not be directly orally taken, and is always limited to be only administered by injection. For example, insulin is the best therapeutic drug for diabetic patients, but can only be administered by injection, and if a person injects 3 times a day for 30 years, it means that he injects more than 3 ten thousand times, and the trouble, inconvenience and pain in the middle are hard to be experienced by normal persons or diabetic patients who do not use insulin therapy. Therefore, the research on the non-injection administration preparation of polypeptides such as insulin is a hot topic of competitive research in the pharmaceutical sciences of all countries in the world and is also an important hope of people.
Through many years of research, non-injection insulin administration modes developed have been advanced, such as oral mucosal absorption, respiratory inhalation administration, oral administration, aerosol, nasal mucosal administration, rectal administration and the like. In particular, mucosal administration is the most widely studied, including oral mucosa, nasal mucosa, and ocular mucosa, and has been regarded as a great hope. However, how to manufacture a stable and easily absorbed medicament preparation absorbed by mucosa is still a technical problem, and the development and the application of the medicament are restricted. Therefore, few such drugs are on the market.
The recombinant human insulin has larger molecular weight and is difficult to be directly absorbed by mucosa, so that the bioavailability of the drug can be ensured only by selecting a proper absorption enhancer and ensuring the combination stability of the drug and the absorption enhancer and the particle size as small as possible.
Chinese patent application CN1264596A discloses a polypeptide drug oral cavity spray, which is prepared by adding propylene glycol and borneol ethanol solution into soybean lecithin, and slowly stirring until the soybean lecithin is completely dissolved; dissolving insulin in 2/3 total amount of phosphate buffer solution containing phenol at pH 6.8-7.8; slowly adding the phosphate buffer solution of the insulin into the propylene glycol solution of the soybean lecithin under continuous stirring, continuously stirring for about 10-30 minutes after the addition is finished, and adding the phosphate buffer solution to the full amount. Through further research, the preparation process has the following defects: taking soybean lecithin, adding ethanol solutions of propylene glycol and borneol, slowly stirring until the soybean lecithin is completely dissolved, and slowly stirring the soybean lecithin and the ethanol solutions of propylene glycol and borneol, wherein the required time is long, the particle size of the obtained soybean lecithin is large, and the research and the quality detection indexes show that: the quality is indirectly reflected by the size of the emulsion particle size, the smaller the particle size is, the higher the light transmittance is, and the smaller the emulsion particle size is, the more sufficient the inclusion is, the better the absorption is, the bioavailability of the medicine is improved, and the curative effect is better.
Disclosure of Invention
In view of the above defects or improvement needs of the prior art, the present invention aims to provide a manufacturing process of an insulin oral spray, which improves the preparation quality of the medicament, shortens the production period, and can provide safer and easier administration modes and medicaments for patients with diabetes by improving the component formula (especially the amount of propylene glycol as a cosolvent) and the preparation process (especially the dissolution treatment of an accelerant therein) of the insulin oral spray.
In order to achieve the above object, according to one aspect of the present invention, there is provided an insulin oral spray comprising insulin and an enhancer, a cosolvent, a flavoring agent, a bacteriostatic agent and a buffer solution, wherein each 1000ml of oral spray comprises: insulin 10,000U-80,000U; 15-45 g of soybean lecithin as an accelerant; 50-120g of propylene glycol and 5-15 ml of ethanol as cosolvent; 1-5 g of borneol as a flavoring agent; 1-4 g of phenol as a bacteriostatic agent; the pH of the buffer solution was 6.8 to 7.8.
According to another aspect of the present invention, there is provided a process for preparing the above oral insulin spray, comprising the steps of:
(1) dissolving soybean lecithin in propylene glycol, shearing and stirring to reach light transmittance of over 40%, adding ethanol solution of borneol, and stirring;
(2) adding the solution obtained in the step (1) into a phosphate buffer solution with the pH value of 6.8-7.8, and then fully shearing and stirring to enable the light transmittance of the solution to reach more than 50%;
(3) adding insulin into phosphate buffer solution, adding phenol, and stirring for dissolving;
(4) and (3) stirring and mixing the solution obtained in the step (2) and the solution obtained in the step (3), fixing the volume to the full volume by using a phosphate buffer solution, and fully mixing to obtain the insulin oral spray.
In a further preferred embodiment of the present invention, the sum of the time of the shear stirring in the step (1) and the time of the shear stirring in the step (2) is not more than 20 hours, and the rotation speed of the shear stirring is 2000rpm to 3000 rpm.
Compared with the prior art, the technical scheme of the invention successfully shortens the process time by using the dissolving method of the accelerant, and more importantly, can well control the particle size of the preparation and improve the quality of the preparation. According to the invention, firstly, the soybean lecithin is taken according to the formula, and propylene glycol is added for shearing, stirring and dissolving (namely, first shearing and stirring), so that the light transmittance of the system reaches more than 40 percent, and the particle size of the soybean lecithin used as an accelerant can be preliminarily regulated and controlled; then adding ethanol solution of borneol, stirring and mixing; then, the obtained mixed solution is added into a phosphate buffer solution for secondary shearing and stirring, so that the light transmittance of the solution reaches more than 50% (the light transmittance reaches more than 50%, namely the particle size of particles with the particle size of 80-90% of the soybean lecithin is less than 60 nm; in addition, the light transmittance can reach 70% at most), and the soybean lecithin can be further refined. Compared with the prior art which needs 30 hours of shearing time, the total shearing time of the invention can be controlled within 20 hours, and the light transmittance is more than 50% (up to 70%), and the better light transmittance also means smaller particle size, smaller particle size of soybean lecithin and easier absorption. The invention can obtain emulsion with smaller grain diameter than the prior art polypeptide medicine oral cavity spray, and the liquid of the spray has high light transmittance. In addition, the invention can be more beneficial to the dissolution of the soybean lecithin by controlling the amount of the propylene glycol used as the cosolvent in each 1000mL of insulin oral spray to be 50-120 g.
The invention can control the total time of the shearing treatment process of the soybean lecithin to be not more than 20 hours, and the shorter the preparation process time is, the more beneficial the product process protection is, such as reducing the air exposure and oxidation of the lecithin; in addition, the insulin oral spray with the specific component formula and the preparation process thereof can obtain emulsion with smaller particle size, and the spray has high liquid transmittance and more complete inclusion and is more beneficial to absorption.
The invention can prepare the insulin oral mucosa spray (which can be used as an oral mucosa absorption medicament), has accurate prescription of the corresponding preparation process and is beneficial to controlling the quality.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention. In addition, the technical features involved in the embodiments of the present invention described below may be combined with each other as long as they do not conflict with each other.
The invention discloses a process for preparing an oral insulin absorption spray, which takes recombinant human insulin to obtain the oral insulin spray as an example, and the specific technical scheme is as follows:
the recombinant human insulin oral spray comprises the following components: as recombinant human insulin, insulin; as the promoter, soybean lecithin; propylene glycol and ethanol as co-solvents; borneol is used as the flavoring agent; phenol is used as the bacteriostatic agent; as the buffer solution, a phosphate buffer solution having a pH of 6.8 to 7.8 is used.
The formula is as follows (per 1000 ml):
Figure BDA0002243325720000041
the preparation process of the recombinant human insulin oral spray comprises the following steps:
step 1: taking soybean lecithin according to the formula, adding propylene glycol, shearing and dissolving to ensure that the light transmittance reaches more than 40%, adding an ethanol solution of borneol, and stirring;
step 2: adding the solution into phosphate buffer solvent solution with pH of 6.8-7.8, and fully shearing to enable the light transmittance of the system to reach more than 50%;
and step 3: adding the recombinant human insulin into a phosphate buffer solution, adding a phenol solution, and stirring for dissolving;
and 4, step 4: mixing the solutions obtained in steps 2 and 3 under stirring, adding phosphate buffer solvent to desired volume, mixing, and packaging (e.g. packaging with quantitative spray pump).
When in use, the recombinant human insulin is sprayed into the oral cavity like aerosol, and the recombinant human insulin is attached to the sublingual mucosa and the oral mucosa and rapidly enters the blood circulation through the mucosa, thus playing the role of reducing blood sugar.
The recombinant human insulin spray is a microemulsion, and the size and the stability of the particle size of the emulsion are directly related to the absorption effect of insulin. The preparation process of the invention improves the formula and the proportion among the medicaments, the accelerator, the cosolvent and the like in the prior art, and simultaneously improves the process preparation method of the prior art, so that the preparation time is shorter, the emulsion is more stable, the particle size is smaller, the inclusion is more sufficient, and the absorption is more favorable.
Compared with the preparation method of the polypeptide medicine oral cavity spray disclosed in the Chinese patent application CN1264596A, the preparation method of the invention has the following relevant data of the product after the preparation process is improved compared with the prior art:
Figure BDA0002243325720000051
Figure BDA0002243325720000061
aiming at the dissolution treatment of an accelerant (namely, soybean lecithin), the invention firstly adds the soybean lecithin into propylene glycol for shearing dissolution, and the shearing dissolution process can ensure that the particle size of the soybean lecithin becomes smaller (the light transmittance of a system reaches more than 40 percent); then adding ethanol solution of borneol and stirring; and the control of the amount of the propylene glycol (namely, the amount of the cosolvent propylene glycol in each 1000mL of the recombinant human insulin oral spray is controlled to be 50-120g) can be more favorable for the refining and dispersion of the soybean lecithin. And the time for dispersing and dissolving is shorter, the particle size is smaller, the emulsion is more stable, the inclusion is more sufficient, the absorption is more facilitated, and the bioavailability of the medicament is improved.
The following are specific examples:
example 1
The process formula is as follows:
Figure BDA0002243325720000062
shearing 25g of soybean lecithin and 50g of propylene glycol, wherein the time is 135min, the rotating speed of the shearing operation is kept between 2000rpm and 3000rpm, and the light transmittance after the shearing treatment meets more than 40 percent; adding ethanol solution of Borneolum Syntheticum, and stirring;
and adding the solution into a phosphate buffer solution, and fully shearing, wherein the rotating speed of shearing operation is kept between 2000rpm and 3000rpm after 610min, so that a dilute solution with the light transmittance of 54.8 percent is obtained, which is greatly superior to the dilute solution with the light transmittance of about 40 percent obtained by adopting the polypeptide medicine oral cavity spray in the prior art.
Example 2
The process formula is as follows:
shearing 25g of soybean lecithin and 75g of propylene glycol for 113min, keeping the rotating speed of shearing operation between 2000rpm and 3000rpm, and ensuring that the light transmittance is over 40 percent after shearing treatment; adding ethanol solution of Borneolum Syntheticum, and stirring;
and adding the solution into a phosphate buffer solution, and fully shearing, wherein the use time is 560min, and the rotating speed of the shearing operation is kept between 2000rpm and 3000rpm to obtain a dilute solution with the light transmittance of 60.8 percent, which is also greatly superior to the dilute solution with the light transmittance of about 40 percent obtained by adopting the polypeptide medicine oral cavity spray in the prior art.
Example 3
The process formula is as follows:
Figure BDA0002243325720000072
shearing 25g of soybean lecithin and 120g of propylene glycol for 128min, keeping the rotating speed of shearing operation between 2000rpm and 3000rpm, and ensuring that the light transmittance is over 40 percent after shearing treatment; adding ethanol solution of Borneolum Syntheticum, and stirring until soybean lecithin is completely dissolved;
and adding the solution into a phosphate buffer solution, and fully shearing, wherein the time is 650min, and the rotating speed of shearing operation is kept between 2000rpm and 3000rpm to obtain a dilute solution with the light transmittance of 52.2 percent, which is also greatly superior to the dilute solution with the light transmittance of about 40 percent obtained by adopting the polypeptide medicine oral cavity spray in the prior art.
The above examples are only for recombinant human insulin, and the formulation of the insulin oral spray component and the manufacturing process thereof in the present invention are also applicable to other types of insulin, such as animal insulin, and insulin analogs known in the art.
It will be understood by those skilled in the art that the foregoing is only a preferred embodiment of the present invention, and is not intended to limit the invention, and that any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the scope of the present invention.

Claims (3)

1. An insulin oral spray comprises insulin, an accelerator, a cosolvent, a flavoring agent, a bacteriostatic agent and a buffer solution, and is characterized in that each 1000ml of oral spray internally comprises: insulin 10,000U-80,000U; 15-45 g of soybean lecithin as an accelerant; 50-120g of propylene glycol and 5-15 ml of ethanol as cosolvent; 1-5 g of borneol as a flavoring agent; 1-4 g of phenol as a bacteriostatic agent; the pH of the buffer solution was 6.8 to 7.8.
2. A process for making an insulin oral spray according to claim 1, comprising the steps of:
(1) dissolving soybean lecithin in propylene glycol, shearing and stirring to reach light transmittance of over 40%, adding ethanol solution of borneol, and stirring;
(2) adding the solution obtained in the step (1) into a phosphate buffer solution with the pH value of 6.8-7.8, and then fully shearing and stirring to enable the light transmittance of the solution to reach more than 50%;
(3) adding insulin into phosphate buffer solution, adding phenol, and stirring for dissolving;
(4) and (3) stirring and mixing the solution obtained in the step (2) and the solution obtained in the step (3), fixing the volume to the full volume by using a phosphate buffer solution, and fully mixing to obtain the insulin oral spray.
3. The method for preparing the insulin oral spray according to claim 2, wherein the sum of the shearing and stirring time in the step (1) and the shearing and stirring time in the step (2) is not more than 20 hours, and the shearing and stirring rotating speed is 2000rpm to 3000 rpm.
CN201911007945.5A 2019-10-22 2019-10-22 Insulin oral spray and preparation process method thereof Pending CN110801515A (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1264596A (en) * 2000-01-07 2000-08-30 华中理工大学 Polypeptide medicine as oral spray
CN1335182A (en) * 2001-08-08 2002-02-13 华中科技大学 Insulin spray for oral cavity and its prepn process

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1264596A (en) * 2000-01-07 2000-08-30 华中理工大学 Polypeptide medicine as oral spray
CN1335182A (en) * 2001-08-08 2002-02-13 华中科技大学 Insulin spray for oral cavity and its prepn process

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
余祥彬: "药剂学与药物动力学实验指导", vol. 1, 科学技术文献出版社, pages: 192 - 196 *

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