JP7853667B2 - Aerosol composition, aerosol product, and method for producing biodegradable polymer thin film - Google Patents

Description

This disclosure relates to aerosol compositions and aerosol products, as well as methods for producing biodegradable polymer thin films.

Conventionally, biocompatible resins, such as biodegradable polymers, have been used in sutures, medical adhesives, and artificial organs. Furthermore, the development of biocompatible thin films using biodegradable polymers that offer high safety, flexibility, transparency, and adhesion to the human body is progressing. For example, Patent Document 1 discloses a laminate of biodegradable polymers using a polylactic acid-based resin that can be used in wound dressings.

International Publication No. 2015/163289

The production of biocompatible thin films using biodegradable polymers, as described in Reference 1, typically employs methods such as spin coating. In the spin coating method, a water-soluble sacrificial layer of PVA is formed by dropping an aqueous solution of, for example, polyvinyl alcohol (PVA) onto a glass or silicon substrate and then rotating the substrate. A solution of the biodegradable polymer dissolved in an organic solvent capable of dissolving the polymer, such as toluene, is then dropped onto this sacrificial layer and spin-coated to form a thin film of the biodegradable polymer. Two layers, the sacrificial layer and the biodegradable polymer, are formed on the substrate. By submerging this substrate in water, the sacrificial layer dissolves, and the biodegradable polymer thin film becomes suspended in the water. This biodegradable polymer thin film is then recovered and applied as a biocompatible thin film to objects to be treated, such as the human body.

However, spin coating presents challenges in terms of productivity, such as the difficulty of mass production, when manufacturing thin films. Furthermore, biocompatible thin films also present challenges in terms of ease of application, as they require pre-application of water to the target object, such as the human body. Moreover, conventional technology has made it difficult to find solvents other than organic solvents and other solvents harmful to the human body that biodegradable polymers can dissolve in. Therefore, the manufacturing method has been limited to the spin coating method for forming biodegradable polymer films, and it has been difficult to extend this to a technique where biodegradable polymer solutions are directly applied to the human body or other objects, and the solvent is evaporated to form biodegradable polymer films.

Another method involves creating an ultrathin film of biodegradable polymer using a spin-coating method, then shredding this ultrathin film and dispersing it in a solution such as water. This dispersion is then applied to the human body, allowing the shredded ultrathin films to layer and form a biodegradable polymer film on the target area. However, because the shredded ultrathin films are layered, uneven film thickness occurs, resulting in a failure to achieve the desired effect. Furthermore, when a dispersion containing the shredded ultrathin films is placed in a spray bottle and sprayed, the nozzle tends to clog due to the shredded ultrathin films, making it unsuitable for film formation by spraying.
This disclosure relates to an aerosol composition that enables the easy and highly productive formation of a thin film of a biodegradable polymer dissolved in a solvent (propellant) that instantly volatilizes when sprayed onto the human body or other objects, on a target object.

This disclosure relates to a propellant containing dimethyl ether and an aerosol composition containing a biodegradable polymer soluble in said dimethyl ether.

This disclosure provides an aerosol composition that allows for the easy and highly productive formation of a thin film of a biodegradable polymer dissolved in a solvent (propellant) that instantly volatilizes when sprayed onto the human body or other objects.

Photograph showing the formation state of a thin film using a scanning electron microscope (photograph used as a substitute for a diagram) Photograph showing the formation state of a thin film using a scanning electron microscope (photograph used as a substitute for a diagram) Photograph showing the formation state of a thin film using a scanning electron microscope (photograph used as a substitute for a diagram) Photograph showing the formation state of the thin film (photograph used as a substitute for a diagram)

Unless otherwise specified, the notation "XX or greater, YY or less" or "XX to YY" indicates a numerical range that includes both the lower and upper limits. When a numerical range is described in steps, the upper and lower limits of each range can be combined in any way.

The aerosol composition contains a propellant containing dimethyl ether and a biodegradable polymer soluble in dimethyl ether. The propellant containing dimethyl ether is highly volatile. The inventors conceived of using the propellant containing dimethyl ether as a solvent for the biodegradable polymer soluble in dimethyl ether.
Due to the high volatility of the propellant containing dimethyl ether, spraying the aerosol composition onto the object to be treated causes the biodegradable polymer dissolved in the dimethyl ether to precipitate, forming a thin film. Observation using a scanning electron microscope (SEM) revealed that the biodegradable polymer forms a particulate coating, which is then layered to form a thin film (Figure 1). Therefore, by using the above aerosol composition, a thin film of biodegradable polymer can be easily formed on the object to be treated with high productivity.

A biodegradable polymer is considered soluble in dimethyl ether if it dissolves in dimethyl ether to the extent that it can form a thin film when the aerosol composition is sprayed. Specifically, this is determined as follows: At 25°C, when 50 mL of dimethyl ether and the biodegradable polymer are filled into a pressure-resistant container (100 mL aerosol glass test bottle), if 0.01 g or more (preferably 0.20 g or more) of the biodegradable polymer dissolves in the dimethyl ether, it is determined that the biodegradable polymer is soluble in dimethyl ether.

The propellant contains dimethyl ether. The propellant may also contain other liquefied gases besides dimethyl ether, to an extent that does not impair the effects of this disclosure. Examples of other liquefied gases include hydrocarbons such as LPG and LNG, and hydrofluoroolefins such as HFO-1234ze.

A compressed gas may be used in combination with the propellant, to the extent that it does not impair the effects of the present disclosure. The compressed gas is not particularly limited, and any known gas that can be used in aerosol products may be used. The compressed gas is preferably at least one selected from the group consisting of carbon dioxide, nitrogen gas, nitrous oxide, argon, helium, and compressed air, more preferably at least one selected from the group consisting of carbon dioxide, nitrogen gas, compressed air, and nitrous oxide, even more preferably at least one selected from the group consisting of carbon dioxide and nitrogen gas, and even more preferably nitrogen gas.
The dimethyl ether content in the propellant is preferably 50.0 to 100.0% by mass, more preferably 70.0 to 100.0% by mass, even more preferably 80.0 to 100% by mass, even more preferably 90.0 to 100.0% by mass, particularly preferably 95.0 to 100.0% by mass, and most preferably 100.0% by mass.

The proportion of propellant in the aerosol composition is preferably 85.0 to 99.9% by mass, more preferably 88.0 to 99.5% by mass, and even more preferably 90.0 to 99.0% by mass.
The content of dimethyl ether in the aerosol composition is preferably 85.0 to 99.9% by mass, more preferably 88.0 to 99.5% by mass, and even more preferably 90.0 to 99.0% by mass.

The aerosol composition contains a biodegradable polymer soluble in dimethyl ether. The biodegradable polymer is a polymer that has the property of being broken down in living organisms. The biodegradable polymer is not particularly limited as long as it is soluble in dimethyl ether; known biodegradable polymers can be used.
Specifically, biodegradable polymers include, for example, polylactic acid, polylactic acid (PLA) resins, polyglycolic acid, aliphatic polyesters such as poly(3-hydroxybutyrate), poly(3-hydroxybutyrate-3-hydroxyvalate), poly(3-hydroxybutyrate-3-hydroxyhexanoate), polyethylene succinate, polybutylene succinate, polybutylene succinate adipate, etc., aliphatic aromatic polyesters such as polyethylene succinate terephthalate, polybutylene succinate terephthalate, polybutylene adipate terephthalate, etc., polyvinyl alcohol or its copolymers, dextran, agarose, pullulan, chitosan, mannan, carrageenan, alginic acid, starches (oxidized Examples include at least one polymer selected from the group consisting of starch, etherified starch, dextrin, etc., polysaccharides such as amylose, amylopectin, pectin, lentinan, hyaluronic acid, hyaluronic acid, hyaluronic acid, cellulose derivatives (methylcellulose, ethylcellulose, carboxymethylcellulose, carboxyethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, etc.), polypeptides such as gelatin, collagen, elastin, albumin, hemoglobin, transferrin, globulin, fibrin, fibrinogen, keratin sulfate, and amino acid homopolymers (e.g., polylysine, polyglutamic acid, polyaspartic acid, etc.), thermoplastic starch, resins made of starch and aliphatic (aromatic) polyester, etc. Biodegradable polymers preferably contain polylactic acid.

Examples of polylactic acid-polyethylene glycol resins include polyethylene glycol-(L) lactide copolymers and polyethylene glycol-(DL) lactide copolymers; and copolymers in which polysaccharides such as dextran are graft-polymerized onto polylactic acid. A commercially available example is the "Takiral" series manufactured by Taki Chemical Co., Ltd.

Polylactic acid preferably contains both D-isomer and L-isomer constituent units.
In polylactic acid, the ratio of the D-isomer in terms of monomer components is preferably 2 to 50 mol%, more preferably 4 to 40 mol%, even more preferably 6 to 30 mol%, even more preferably 8 to 20 mol%, particularly preferably 10 to 15 mol%, and especially preferably 12 mol%.
Furthermore, the L-isomer ratio in terms of monomer components in polylactic acid is preferably 50 to 98 mol%, more preferably 60 to 96 mol%, even more preferably 70 to 94 mol%, even more preferably 80 to 92 mol%, particularly preferably 85 to 90 mol%, and especially preferably 88 mol%. Within the above range, the solubility of polylactic acid is improved. The polylactic acid is preferably poly-DL-lactic acid.

It is known that so-called poly-L-lactic acid, with an L-isomer ratio of approximately 100%, is insoluble in dimethyl ether. However, through our research, we have found that polylactic acid becomes soluble in dimethyl ether when the D-isomer ratio in the polylactic acid is at a certain level. This is because, although poly-L-lactic acid is classified as a crystalline polymer due to its isotactic stereoregularity, an increase in the D-isomer ratio inhibits the formation of crystalline regions in the L-lactic acid chain, leading to amorphous properties. We believe that this result in improved solubility through solvation with dimethyl ether.

The content of the biodegradable polymer soluble in dimethyl ether in the aerosol composition is not particularly limited, and should be within a range that allows for the formation of a thin film of the biodegradable polymer. The content is preferably 0.1 to 15.0% by mass, more preferably 0.5 to 12.0% by mass, and even more preferably 1.0 to 10.0% by mass. Within this range, film-forming properties are improved.

The aerosol composition preferably contains a plasticizer that plasticizes the biodegradable polymer. The plasticizer refers to a substance that imparts plasticity to the biodegradable polymer, and is not particularly limited as long as it has such properties; known plasticizers can be used.
By incorporating such plasticizers into the aerosol composition, the plasticity of the biodegradable polymer is increased, resulting in improved smoothness of the resulting biodegradable polymer thin film and enabling the creation of a more transparent thin film. Therefore, for example, when the aerosol composition is applied to the human body, the thin film is less noticeable, which is preferable from an aesthetic standpoint.
Figure 2 shows SEM images of an aerosol composition containing oxybenzone (OB), which functions as both an ultraviolet absorber and a plasticizer, after spraying. It is believed that oxybenzone acts as a plasticizer, as the smoothness of the thin film after spraying is improved.

Examples of plasticizers for plasticizing biodegradable polymers include oxybenzone and at least one compound selected from the group consisting of oily components and alcohols.
The oily component may be at least one compound selected from the group consisting of ester compounds.
Examples of ester compounds include fatty acid esters such as isopropyl myristate, butyl myristate, isocetyl myristate, octyldodecyl myristate, butyl stearate, ethylhexyl stearate, isopropyl isostearate, isopropyl palmitate, ethylhexyl palmitate, ethyl linoleate, butyloctyl salicylate, cetyl ethylhexanoate, and ethyl olive fatty acid (ethyl oleate); triethylhexanoin, propylene glycol monocaprylate, propylene glycol dicaprylate, trimethylolpropane triethylhexanoate, and trimethylolpropane triisostearate. Examples include polyhydric alcohol fatty acid esters such as caprylic/capric triglyceride; polybasic acid esters such as diisopropyl adipate, diisopropyl sebacate, and diethyl sebacate; and dimer acid esters such as dimer dilinoleyl (phytosteryl/isostearyl/cetyl/stearyl/behenyl), dimer dilinoleyl dimer dilinoleate, dimer dilinoleyl bis(behenyl/isostearyl/phytosteryl), di(isostearyl/phytosteryl) dimer dilinoleate, hydrogenated castor oil dimer dilinoleate, and diglyceryl isostearate dimer dilinoleate.

The alcohol is selected from the group consisting of, for example, lower alcohols such as ethanol, propanol, and isopropanol; higher alcohols such as cetyl alcohol, stearyl alcohol, hexyldecanol, isostearyl alcohol, octyldodecanol, and decyltetradecanol; and polyhydric alcohols such as 1,3-butylene glycol, propylene glycol, isopentyl diol, pentylene glycol, 1,3-propanediol, polyethylene glycol, and glycerin, to the extent of at least one.

The proportion of plasticizer in the aerosol composition is not particularly limited, as the rate of change in plasticity differs depending on the combination of biodegradable polymer and plasticizer. It can be appropriately adjusted according to the desired plasticity of the biodegradable polymer. For example, the proportion of plasticizer in the aerosol composition is preferably 0.1 to 10.0% by mass, more preferably 0.2 to 5.0% by mass, even more preferably 0.3 to 3.0% by mass, and even more preferably 0.5 to 2.0% by mass.

The mass ratio of the biodegradable polymer and plasticizer (biodegradable polymer:plasticizer) in the aerosol composition may be appropriately adjusted to match the desired plasticity of the biodegradable polymer. This mass ratio is preferably 10:1 to 1:10, more preferably 5:1 to 1:5, and even more preferably 3:1 to 1:3.

The aerosol composition may contain known active ingredients and additives that can be used in pharmaceuticals, quasi-drugs, and cosmetics, to the extent that they do not impair the above-mentioned effects. For example, it may contain fragrances, antioxidants, preservatives, pH adjusters, thickeners, humectants, skin protectants, vitamins, various extracts, deodorants, odor inhibitors, cooling agents, antiperspirants, UV absorbers, UV scattering agents, anti-inflammatory and analgesic agents, anti-inflammatory agents, antipruritics, bactericides, antibacterial agents, antifungal agents, topical skin preparations, insect repellents, antistatic agents, etc. It is preferable that the active ingredients and additives are soluble in dimethyl ether.

By spraying the aerosol composition of this disclosure, it is possible to easily wrap the object to be treated with a thin film of biodegradable polymer. By including an active ingredient in the aerosol composition, the active ingredient can be included in the thin film of biodegradable polymer. The biodegradable polymer has the ability to release active ingredients and other substances slowly, and is resistant to external factors such as friction, rain, and wind, so it can continuously supply active ingredients and other substances to the object to be treated while keeping them stable for a long time.
The content of the active ingredient in the aerosol composition is not particularly limited and can be appropriately changed depending on the purpose of the ingredient used, but for example, 0.1 to 10.0% by mass is preferred, and 0.2 to 5.0% by mass is more preferred.

Examples of active ingredients and other additives include the following:
UV absorbers (e.g., oxybenzone, avobenzone); preservatives (e.g., parabens, phenoxyethanol, methyl parahydroxybenzoate); pH adjusters (e.g., citric acid, lactic acid, triethanolamine, KOH, NaOH); antioxidants (e.g., ascorbic acid, thiotaurine); antibacterial agents (e.g., chitosan); urea; minerals such as calcium, iron, and sodium; pigments; dyes; silicone oils such as dimethicone; chelating agents such as EDTA-2Na and sodium citrate; antiviral agents (e.g., acyclovir); antifungal agents (e.g., itraconazole); corticosteroids (e.g., betamethasone and its esters); nonsteroidal antimicrobial agents Anti-inflammatory drugs (e.g., indomethacin, loxoprofen); anti-allergic drugs (e.g., diphenhydramine, emedastine fumarate); bronchodilators (e.g., tulobuterol); anti-angina drugs (e.g., nitroglycerin, isosorbide dinitrate); antihypertensive drugs (e.g., bisoprolol); anti-overactive bladder drugs (e.g., oxybutynin hydrochloride); anti-dementia drugs (e.g., rivastigmine); anti-Parkinson's disease drugs (e.g., rotigotine); psychostimulants - drugs for attention deficit hyperactivity disorder (e.g., methylphenidate); SDA - drugs for schizophrenia (e.g., blonanserin); female hormones (e.g., estradiol); opioids (e.g., fentanyl,
Buprenorphine, etc.; smoking cessation aids (nicotine), etc.

Next, we will discuss aerosol products.
Aerosol products are
A container filled with an aerosol composition, and a dispensing mechanism provided in the container for dispensing the aerosol composition.
The discharge mechanism and container are not particularly limited and known ones can be used. The container only needs to be able to withstand the pressure of the propellant, and known containers made of resin, metal, glass, etc., can be used.

The pressure (gauge pressure) inside the container of an aerosol product is not particularly limited. The propellant should be filled into the aerosol container such that the pressure inside the container (gauge pressure) at 25°C is, for example, 1 MPa or less.

The discharge form of the aerosol product is not particularly limited, but it is preferably spray or mist. The aerosol composition is preferably a spray composition that is ejected in a spray or mist form. The discharge mechanism of the aerosol product is also not particularly limited; for example, a straight-type or mechanical breakup-type nozzle is used. The aerosol product may employ a known actuator capable of spraying in a spray or mist form. The nozzle diameter is preferably 0.1 to 2.5 mm, more preferably 0.2 to 1.5 mm, and even more preferably 0.3 to 1.0 mm.

The method for manufacturing aerosol compositions and aerosol products is not particularly limited, and known methods can be employed. For example, an aerosol product can be obtained by filling a pressure vessel with a biodegradable polymer and dimethyl ether, and optionally a plasticizer, active ingredient and other ingredients in any proportion.
Aerosol compositions and aerosol products can be used, for example, in applications such as topical skin preparations (including adhesive bandages), cosmetics, pharmaceuticals, and quasi-drugs.

This disclosure provides a method for producing a biodegradable polymer thin film. The method for producing a biodegradable polymer thin film (excluding medical procedures) comprises the steps of preparing the aerosol product and spraying the aerosol product onto the object to be treated to form a biodegradable polymer thin film. The object to be treated is not particularly limited and can include, for example, organs such as skin in living organisms such as humans and animals.

The present invention will be described in detail below with reference to examples. However, the present invention is not limited to the embodiments described below.

<Examples 1-30, Comparative Examples 1-11>
Each raw material was filled into a pressure-resistant container (100 mL aerosol glass test bottle) and mixed according to the formulations (mass%) shown in Tables 1 to 3 to obtain each aerosol product.

Examples 16 to 30, in which a plasticizer was added, yielded a more transparent film than Example 1 in the evaluation of film formation properties.

The materials used are as follows. In a dissolution test conducted at 25°C, where 50 mL of dimethyl ether and biodegradable polymer were filled into a pressure-resistant container (100 mL aerosol glass test bottle), Poly(D,L-lactic acid) dissolved at a rate of 0.01 g or more. On the other hand, Poly(L-lactic acid), Poly(D,L-lactide-co-glycolide), and Polycaprolactone dissolved at a rate of less than 0.01 g.
Poly(D,L-lactic acid) (D-isomer ratio: 12 mol%, L-isomer ratio: 88 mol%, NatureWorks LLC)
Poly(L-lactic acid) (Polysciences Inc.)
Poly(D,L-lactide-co-glycolide) (Polysciences Inc.)
Polycaprolactone (Polysciences Inc.)
LPG (Liquefied Petroleum Gas)
DME (dimethyl ether)
HFO 1234-ze (trans-1,3,3,3-tetrafluoropropene)
Oxybenzone (Tokyo Chemical Industries Co., Ltd.)
Avobenzone (Tokyo Chemical Industries Co., Ltd.)
1,3-Butylene glycol (KH Neochem Co., Ltd.)
Propylene glycol (ADEKA Corporation)
PEG-300 (NOF Co., Ltd.)
Isopropyl myristate (Excepearl IPM) (Kao Corporation)
99% Ethanol (Nippon Alcohol Sales Co., Ltd.)

The following evaluations were performed on the obtained aerosol products. The results are shown in Tables 1 to 3.
(1) Solubility of biodegradable polymers In the obtained aerosol product, it was confirmed whether the biodegradable polymer was soluble in dimethyl ether.
A: The biodegradable polymer dissolved in dimethyl ether.
B: The biodegradable polymer dissolved in dimethyl ether, but some remained undissolved.
C: The biodegradable polymer did not dissolve in dimethyl ether.

(2) Film-forming properties The film-forming properties of each aerosol product were evaluated when the aerosol composition was sprayed. Products in which the biodegradable polymer did not dissolve in dimethyl ether were not evaluated.
Specifically, under conditions of 25°C, a misting button (nozzle diameter φ0.5 mm, straight type (D390W0520D"3"-A, Mitani Valve Co., Ltd.)) was used to spray the aerosol product onto the back of the hand for approximately 1 second to check whether a protective film had formed.
A: A coating was formed.
B: No coating was formed.

Furthermore, Figure 1 shows a scanning electron microscope (SEM) image (PLA in DME) of the aerosol product from Example 1 when sprayed onto a slide glass from a distance of 15 cm for 0.5 seconds, 1 second, 2 seconds, and 3 seconds using a mist-type button (nozzle diameter φ0.5 mm, straight type (D390W0520D"3"-A, Mitani Valve Co., Ltd.)). The biodegradable polymer was observed to form a particulate coating and accumulate over time.

Similarly, Figure 2 shows the results when using the aerosol product of Example 6 (OB-PLA in DME). In Example 6, it is thought that oxybenzone (OB), as an ultraviolet absorber, also functions as a plasticizer that plasticizes the biodegradable polymer, resulting in a coating film with higher smoothness and transparency.

Similarly, Figure 3 shows the results when the aerosol product of Example 7 was used (AB-PLA in DME). In Example 7, avobenzone (AB) was used as the ultraviolet absorber. Since AB does not appear to act as a plasticizer, similar to Example 1, it was observed that the biodegradable polymer formed a particulate coating film and accumulated.

Figure 4 shows the appearance of slide glasses after spraying the aerosol products of Examples 1, 6, and 7 (1: Example 1, (2): Example 6, (3): Example 7). The thin film of Example 6 (2), which contains a plasticizer, exhibits less opacity and higher transparency compared to the others.

Claims (5)

Aerosol composition,
The aerosol composition contains a propellant containing dimethyl ether and a biodegradable polymer soluble in the dimethyl ether .
The biodegradable polymer is poly-DL-lactic acid,
In the poly-DL-lactic acid, the proportion of the D-isomer in terms of monomer components is 2 to 50 mol%,
In the poly-DL-lactic acid, the proportion of the L-isomer in terms of monomer components is 50 to 98 mol%,
An aerosol composition characterized in that the content of dimethyl ether in the aerosol composition is 85.0 to 99.9% by mass . The aerosol composition according to claim 1 , wherein the content of the biodegradable polymer in the aerosol composition is 0.1 to 15.0% by mass. The aerosol composition according to claim 1 or 2 , wherein the aerosol composition further contains a plasticizer that plasticizes the biodegradable polymer. A container filled with an aerosol composition, and an aerosol product provided in the container and having a dispensing mechanism for dispensing the aerosol composition,
An aerosol product wherein the aerosol composition is the aerosol composition described in any one of claims 1 to 3 . A method for producing a biodegradable polymer thin film on an object to be treated (excluding medical procedures),
A method for producing a biodegradable polymer thin film, comprising the steps of preparing the aerosol product described in claim 4 , and spraying the aerosol product onto an object to be treated to form a thin film of a biodegradable polymer.