JPH0331164B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention resides in a therapeutic adhesive tape or sheet. A therapeutic adhesive tape or sheet having a pressure-sensitive adhesive layer mixed with a therapeutic drug as a base material is applied to the skin, and treatment is performed using the drug that oozes from the pressure-sensitive adhesive layer. Conventional therapeutic adhesive tapes or sheets include, for example, pressure-sensitive adhesives made of a copolymer of acrylic acid alkyl ester and acrylic acid mixed with a drug, acrylic esters or methacrylic acid having an ether bond in the molecule. There are pressure-sensitive adhesives made of copolymers of active monomers such as esters, alkyl esters of acrylic acid or methacrylic acid, and active monomers such as acrylic acid or methacrylic acid, in which a drug is mixed. However, in such pressure-sensitive adhesives, acrylic acid or methacrylic acid is used as a copolymer component in order to obtain the internal cohesive force necessary to prevent the pressure-sensitive adhesive from adhering to the adherend (adhesive residue) and preventing slippage. Because of this, they tend to cause chemical reactions with drugs and impair their efficacy. For this reason, the use of pressure-sensitive adhesives made of polymers of acrylic acid alkyl esters and/or methacrylic acid alkyl esters that do not have chemically active groups has been considered, but the A sufficient internal cohesive force could not be obtained, and there was a risk that a large amount of acrylic acid alkyl ester, which does not participate in polymerization, remained in the polymer, causing deterioration of the drug. The gist of the present invention is to provide a therapeutic adhesive tape or sheet in which a base material is provided with a pressure-sensitive adhesive layer containing a drug, in which the pressure-sensitive adhesive is a copolymer of an alkyl methacrylate and an alkyl acrylate. The amount of components involved in the copolymerization of methacrylic acid alkyl ester and acrylic acid alkyl ester is 40:60 to 60 in molar ratio.
The average carbon number of the alkyl groups of the methacrylic acid alkyl ester and acrylic acid alkyl ester in the copolymer is 3 to 5, and the average carbon number of the alkyl group of the methacrylic acid alkyl ester is 6. The number of carbon atoms in the alkyl group of the acrylic acid alkyl ester is 4 or less, and the residual monomer amount of the methacrylic acid alkyl ester having an alkyl group having 4 or more carbon atoms and the acrylic acid alkyl ester having 5 or more carbon atoms is A therapeutic adhesive tape or sheet, characterized in that the amount is 0.2% by weight or less. Next, the therapeutic adhesive tape or sheet of the present invention will be explained in more detail. The base material used in the present invention is preferably a flexible material such as polyethylene, ethylene-vinyl acetate copolymer, soft polyvinyl chloride, or cellophane, and the thickness of the base material is 0.02 to 0.15 mm. A range is preferred. The base material is subjected to corona discharge treatment, plasma treatment, primer coating, etc., if necessary, in order to increase the adhesion with the pressure-sensitive adhesive layer. A pressure sensitive adhesive layer is formed on the substrate. The pressure-sensitive adhesive has a copolymer of an alkyl methacrylate and an alkyl acrylate as a constituent component. In the copolymer whose constituent components are alkyl methacrylate and alkyl acrylate,
The amount of residual monomer is much lower than in the case of these homopolymers. The reason why residual monomers in adhesives become a problem is that when the drug is susceptible to deterioration, such as a steroid hormone, the residual monomers can cause deterioration of the drug. Incidentally, the remaining monomers include both easily volatile monomers and slow volatile monomers. Easily volatile monomers are monomers that volatilize together with the solvent during the process in which the adhesive solution is applied to the base material and dried, so that virtually no residue remains; methacrylic acid having an alkyl group having 3 or less carbon atoms Alkyl esters and acrylic acid alkyl esters having 4 or less carbon atoms correspond to this. A slow-volatile monomer is a monomer that remains as it is without being substantially volatilized during the process in which an adhesive solution is applied to a base material and dried, and is an alkyl methacrylate having an alkyl group having 4 or more carbon atoms. Ester and acrylic acid alkyl ester having an alkyl group having 5 or more carbon atoms correspond to this. Since the easily volatile monomer is volatilized during the drying process when forming the pressure-sensitive adhesive layer, it has almost no effect on the deterioration of the agent. However, since the slow-volatile monomer is not volatilized during the drying process when forming the pressure-sensitive adhesive layer, it causes deterioration of the chemicals present in the pressure-sensitive adhesive layer. Therefore, it is necessary to form a pressure-sensitive adhesive layer with a small residual amount of slow-volatile monomer, and the present inventors also studied the composition of the adhesive from this perspective, and found that methacrylic acid alkyl ester and acrylic acid The following findings were obtained regarding the composition of copolymers with acid alkyl esters. In other words, the molar ratio of the components involved in the copolymerization of alkyl methacrylate and alkyl acrylate is 40:
The ratio is in the range of 60 to 15 to 85, and the average carbon number of the alkyl groups of the methacrylic acid alkyl ester and acrylic acid alkyl ester in the copolymer is 3 to 5, and the average number of carbon atoms of the alkyl groups of the methacrylic acid alkyl ester is 3 to 5. The number of carbon atoms is 6 or less,
When the average number of carbon atoms in the alkyl group of the acrylic acid alkyl ester is 4 or less, methacrylic acid alkyl ester having an alkyl group having 4 or more carbon atoms and acrylic acid alkyl ester having 5 or more carbon atoms are slow-volatile monomers. The amount of residual monomer
It was found that it was possible to maintain the content by polymerization to an astonishingly low level of 0.2% by weight or less. The amount of components involved in the copolymerization of alkyl methacrylate and alkyl acrylate is in a molar ratio of 40:60 to 15:85. This is because if the amount of alkyl methacrylate is greater than the above ratio, the average number of carbon atoms in the alkyl group of the alkyl methacrylate must be 6 or more in order to maintain the physical properties of the pressure-sensitive adhesive, and after polymerization, If the residual amount of the slow-volatile monomer is more than 0.2% by weight, or conversely, if the amount of the alkyl methacrylate is less than the above ratio, the cohesive strength of the pressure-sensitive adhesive will be insufficient, and at the same time the alkyl acrylate will This is because the amount of residual monomer becomes so large that it often cannot be completely volatilized by applying and drying the pressure-sensitive adhesive. Furthermore, the average number of carbon atoms in the alkyl groups of the methacrylic acid alkyl ester and the acrylic acid alkyl ester in the copolymer is 3 to 5. This is because the adhesion to adherends such as the skin and internal cohesive force are suitable, and good drug release properties are also obtained. The average number of carbon atoms in the alkyl group of the methacrylic acid alkyl ester is said to be 6 or less. As a result, the amount of slow-volatile monomer of alkyl methacrylate remaining in the pressure-sensitive adhesive can be made extremely small. The average number of carbon atoms in the alkyl group of the acrylic acid alkyl ester is 4 or less. As a result, the amount of slow-volatile acrylic acid alkyl ester monomer remaining in the pressure-sensitive adhesive can be made extremely small. The ester residues in the methacrylic acid alkyl ester and acrylic acid alkyl ester include, for example, a methyl group, an ethyl group, a propyl group,
Isopropyl group, n-butyl group, isobutyl group,
n-pentyl group, isopentyl group, 2-methylbutyl group, n-hexyl group, 2-methylpentyl group, 3-methylpentyl group, 2-ethylbutyl group, n-octyl group, isooctyl group, 2-ethylhexyl group, nonyl group , n-decyl group, lauryl group, etc. Particularly preferred methacrylic acid alkyl esters include methyl methacrylate, ethyl methacrylate, propyl methacrylate, isopropyl methacrylate, butyl methacrylate, isobutyl methacrylate, 2-ethylhexyl methacrylate, n-octyl methacrylate, isodecyl methacrylate, lauryl methacrylate, and the like. Examples of the acrylic acid alkyl ester include n-butyl acrylate and isobutyl acrylate. Practical performance of the pressure-sensitive adhesive can be obtained by using the above-mentioned constituent components, but if a higher internal cohesive force is required, for example, slight crosslinking can be carried out during polymerization. Micro-crosslinking is different from crosslinking using ordinary chemical crosslinking agents, which creates a highly three-dimensional structure.
Refers to a substance with a slight degree of crosslinking. Examples of the slight crosslinking agent include 1,4-butanediol di(meth)acrylate, 1,6-hexanediol di(meth)acrylate, polyethylene glycol di(meth)acrylate, and polypropylene glycol di(meth)acrylate. , 0.005 based on the total amount of copolymerization components of methacrylic acid alkyl ester and acrylic acid alkyl ester
It is preferably used within the range of 0.2 mol %. For example, when the base material is made of ethylene-vinyl acetate copolymer, etc., vinyl acetate may be added to the main component of the pressure-sensitive adhesive in order to improve the adhesion of the pressure-sensitive adhesive layer to the base material. It is also possible to copolymerize up to 20 mol%. Furthermore, for the purpose of increasing hygroscopicity and preventing peeling for those with a sweaty constitution or during periods of excessive sweating in the summer, a water-absorbing component such as diacetone acrylamide or vinyl pyrrolidone can be copolymerized in a range of 20 mol%. . In the production of pressure-sensitive adhesives, solution polymerization, emulsion polymerization, suspension polymerization, etc. can be carried out using ordinary radical polymerization catalysts such as azobis-based compounds and peroxide-based compounds, but this is a post-process. Considering the mixing and dissolving process of the drug, solution polymerization is optimal. For example, each component constituting the copolymer and a solvent such as ethyl acetate are added to a reaction vessel to form a solution with the highest possible concentration (approximately 60 to 90% by weight), and the atmosphere inside the reaction vessel is replaced with nitrogen gas. The temperature is raised with stirring, and at a temperature of 60 to 80°C, a solution of the radical generating catalyst dissolved in the same solvent is dropped or injected in portions, and only the solvent is added as the viscosity increases. Suppresses viscosity and reduces overall viscosity from 20 to
Polymerization is completed in 40 hours. To obtain therapeutic adhesive tapes or sheets,
A therapeutic drug is mixed into a pressure-sensitive adhesive solution to form a uniform solution, which is then applied to the base material, the solvent component is volatilized, and the mixture is heated to about 160°C and dried to form a pressure-sensitive adhesive layer. A protective release paper may be pressure-bonded, or a pressure-sensitive adhesive solution mixed with a drug may be applied to the release paper, and a pressure-sensitive adhesive solution containing no drug may be applied to the base material. A therapeutic adhesive tape or sheet may be prepared by applying a drug solution to the surface of the pressure-sensitive adhesive layer by spraying or coating it before or after drying at about 160° C., and then pressing a release paper onto the surface. As a drug, for example, when steroid hormones such as hydrocortisone, brednisolone, flumethasone, β-methasone, dexamethasone, triamcinolone, fluocinolone, etc. or their acetonides are used, particularly advantageous results are obtained in terms of increasing the stability of the drug. can get. According to the present invention, the chemistry between a methacrylic acid alkyl ester having an alkyl group having 4 or more carbon atoms and an acrylic acid alkyl ester having 5 or more carbon atoms, which are slow volatile monomers remaining in the pressure-sensitive adhesive layer, and a drug. The drug's efficacy can be maintained stably for a long period of time without causing any chemical reactions. Furthermore, according to the present invention, the adhesion and peelability when applied to the skin, as well as the drug release properties, are also good. Example 1 Lauroyl methacrylate 30.5 g (0.12 mol) n-butyl methacrylate 51.1 g (0.36 mol) n-butyl acrylate 92.2 g (0.72 mol) 1,6-hexane glycol dimethacrylate
0.03g (0.01mol%) Ethyl acetate 60g During the polymerization reaction, 0.6g of azobisisobutyronitrile as a polymerization catalyst was added as a 100ml ethyl acetate solution in 5 portions during the polymerization reaction, and nitrogen was added. Polymerization was carried out at 65°C for 28 hours under air flow. During this time, stirring was continued while adding ethyl acetate to prevent an excessive increase in viscosity, and the solution was finally adjusted to a 24.8% by weight ethyl acetate solution. The slow volatile residual monomers in the obtained adhesive solution were measured by gas chromatography and found that lauric acid methacrylate was 0.08% by weight and n-butyl methacrylate was 0.01% by weight or less. Further, n-butyl acrylate, which is an easily volatile monomer, was 1.3% by weight. This adhesive has a component molar ratio of methacrylic acid alkyl ester (lauroyl methacrylate, n-butyl methacrylate) to acrylic acid alkyl ester (n-butyl acrylate) of 40:60, and the average carbon number of the alkyl group of the methacrylic acid alkyl ester is 6. The average carbon number of the entire alkyl group was 4.8. An ethyl alcohol solution of prednisolone was added to the above polymer solution at a ratio of 1 g of prednisolone per 100 g of polymer and mixed to obtain a coating solution. A 25μ thick polyester film with corona discharge treatment on one side is used as the base film.
The above coating solution was applied to the treated surface using a knife coater so that the weight of the dried adhesive layer was 0.4 g per 100 cm ² and dried at 70°C for 30 minutes. Afterwards, silicone release paper was applied to the adhesive surface to protect it. The adhesive tape for treatment was obtained by pressure bonding. This therapeutic adhesive sheet contained 40 μg of prednisolone in the adhesive layer per cm ² . Next, a drug extraction test, an adhesion test, and a practical skin adhesion test were conducted. The results are shown in the Example 1 column of Table 1. Drug extraction test Samples with a diameter of 60 mm were punched out from therapeutic adhesive sheets, stored at a temperature of 20°C and humidity of 60% RH for 30 days, and sealed and packaged with synthetic resin laminated aluminum foil.
For a total of three types of samples that were accelerated for 10 days and 30 days at 60°C and 70% RH, the release paper was removed and the extract solution (water:alcohol = 95:5)
The amount of drug extracted into the solution was measured using a comparative quantitative method using liquid chromatography, and the amount of drug originally contained (1.13
It was calculated as the extraction rate per mg). Adhesive strength test A 15 mm x 15 cm sample was cut from the therapeutic adhesive sheet, pressed onto a stainless steel plate polished with sandpaper, and peeled off at a peeling speed of 300 mm/min with a 180° turn to measure the adhesive strength. Practical skin adhesive adhesion: A 15 mm x 15 mm sample was cut from the therapeutic adhesive sheet, applied to the skin, and the adhesion state was observed 24 hours later. A: It is stuck in its original position and there is no abnormality. B: Adhesive protrudes by 1 mm or more at the periphery. C: Adhesive is noticeably protruding from the periphery or the adhesion position is misaligned. D: The sample has peeled off. Peelability: The sensation when peeling off the sample adhered to the skin was classified as follows. ◎ I feel pain because the adhesive is too strong. 〇 Painless. Example 2 Isodecyl methacrylate 22.6 g (0.1 mol) Isobutyl methacrylate 36.9 g (0.26 mol) n-butyl acrylate 107.5 g (0.84 mol) Ethyl acetate 60 g To the mixture of the above components, azobisisobutylene was added as a polymerization catalyst. A solution of 0.6 g of lonitrile in 100 ml of ethyl acetate was added in 5 portions during the polymerization reaction, and polymerization was carried out at 60° C. for 38 hours under a nitrogen stream. During this time, stirring was continued while adding ethyl acetate to prevent excessive increase in viscosity, and finally a 26.9% by weight ethyl acetate solution was prepared. As a result of measuring the slow volatile residual monomer in the obtained adhesive solution by gas chromatography, it was found that isodecyl methacrylate was 0.06% by weight;
Isobutyl methacrylate was 0.01% by weight or less. Further, the amount of n-butyl acrylate, which is an easily volatile monomer, was 1.1% by weight. This adhesive is
The molar ratio of the components is 30:70 to methacrylic acid alkyl ester (isodecyl methacrylate, isobutyl methacrylate) to acrylic acid ester (n-butyl acrylate), the average number of carbon atoms in the alkyl group of the methacrylic acid alkyl ester is 5.7,
The average carbon number of all the alkyl groups was 4.5. Next, a therapeutic adhesive sheet was prepared in the same manner as in Example 1, and a drug extraction test, an adhesive strength test, and a practical skin adhesion test were conducted in the same manner as in Example 1. The results are shown in the column of Example 2 in Table 1. Example 3 2-ethylhexyl methacrylate
18.4g (0.1mol) n-butyl methacrylate 28.4g (0.2mol) n-butyl acrylate 115.2g (0.9mol) 1,6-hexane glycol dimethacrylate
0.046g (0.015mol%) Ethyl acetate 60g A solution of 0.8g of azobisisobutyronitrile as a polymerization catalyst in 100ml of ethyl acetate was added in 10 portions during the polymerization reaction to the mixed solution of each of the above components, and a nitrogen stream was added. Polymerization was then carried out at 60°C for 40 hours. During this time, stirring was continued while adding ethyl acetate to prevent an increase in viscosity, and finally a 23.1% by weight ethyl acetate solution was obtained. As a result of measuring the slow volatile residual monomer in the obtained adhesive solution by gas chromatography, it was found that 2-ethylhexyl methacrylate
The content was 0.04% by weight, and the content of n-butyl methacrylate was 0.01% by weight or less. The amount of n-butyl acrylate, a readily volatile monomer, was 1.4% by weight. This adhesive has a component molar ratio of alkyl methacrylate (2-ethylhexyl methacrylate, n-butyl acrylate) to alkyl acrylate (n-butyl acrylate).
was 25:75, the average carbon number of the alkyl group of the methacrylic acid alkyl ester was 5.3, and the average carbon number of the entire alkyl group was 4.3. Next, a therapeutic adhesive sheet was prepared in the same manner as in Example 1, and a drug extraction test, an adhesive strength test, and a practical skin adhesion test were conducted in the same manner as in Example 1. The results are shown in the Example 3 column of Table 1. Example 4 n-Butyl methacrylate 17.0 g (0.12 mol) Methyl methacrylate 12.0 g (0.12 mol) n-butyl acrylate 102.4 g (0.8 mol) Isobutyl acrylate 20.5 g (0.16 mol) Ethyl acetate 45 g To the mixture of the above components On the other hand, a solution of 1.0 g of lauroyl peroxide in 100 ml of ethyl acetate as a polymerization catalyst was added in 10 times during the polymerization reaction, and the mixture was heated for 65 minutes under a nitrogen stream.
Polymerization was carried out at ℃ for 30 hours. During this time, stirring was continued while adding ethyl acetate to prevent an excessive increase in viscosity, and the solution was finally adjusted to a 27.0% by weight ethyl acetate solution. The slow volatile residual monomer in the obtained adhesive solution was measured by gas chromatography and found to be 0.01% by weight of n-butyl methacrylate. The easily volatile monomers n-butyl acrylate and isobutyl acrylate contained a total of 1.6% by weight, and methyl methacrylate contained 0.01% by weight. This adhesive has a molar ratio of methacrylic acid alkyl ester (n-butyl methacrylate, methyl methacrylate) to acrylic acid alkyl ester (n-butyl acrylate, isobutyl acrylate) of 20:80, and the average carbon of the alkyl group of the methacrylic acid alkyl ester The average carbon number of all alkyl groups having a number of 2.5 was 3.7. Next, a therapeutic adhesive sheet was prepared in the same manner as in Example 1, and a drug extraction test, an adhesive strength test, and a practical skin adhesion test were conducted in the same manner as in Example 1. The results are shown in the column of Example 4 in Table 1. Example 5 Isobutyl methacrylate 14.2 g (0.1 mol) Methyl methacrylate 8.0 g (0.08 mol) n-butyl acrylate 64.0 g (0.5 mol) Isobutyl acrylate 66.6 g (0.52 mol) 1,6-hexane glycol dimethacrylate
0.04 g (0.013 mol%) Ethyl acetate 45 g A solution of 0.8 g of azobisisobutyronitrile as a polymerization catalyst in 100 ml of ethyl acetate was added in 10 portions during the polymerization reaction to the mixture of the above components, and a nitrogen stream was added. Polymerization was then carried out at 60°C for 35 hours. During this time, stirring was continued while adding ethyl acetate to prevent an excessive increase in viscosity, and the solution was adjusted to an ethyl acetate solution having a concentration of 25.8% by weight. The slow volatile residual monomer in the obtained adhesive solution was measured by gas chromatography and found to be 0.02% by weight of isobutyl methacrylate. In addition, the total amount of easily volatile monomers n-butyl acrylate and isobutyl acrylate was 1.8% by weight, and methyl methacrylate was 0.01% by weight.
It was in weight%. This adhesive has a molar ratio of methacrylic acid alkyl ester and acrylic acid alkyl ester of 15:85.
The average carbon number of the alkyl group of the methacrylic acid alkyl ester was 2.7, and the average carbon number of the entire alkyl group was 3.8. Next, a therapeutic adhesive sheet was prepared in the same manner as in Example 1, and further tested in the same manner as in Example 1 for drug extraction properties, adhesive strength, and practical skin adhesion. The results are shown in the column of Example 5 in Table 1. Comparative example 1 2-ethylhexyl acrylate
110.4 g (0.6 mol) n-butyl acrylate 76.8 g (0.6 mol) Ethyl acetate 60 g To the mixture of the above components, a solution of 0.6 g of azobisisobutyronitrile in 100 ml of ethyl acetate was added as a polymerization catalyst during the polymerization reaction. The mixture was charged in batches and polymerized at 60°C for 40 hours under nitrogen flow. During this time, stirring was continued while adding ethyl acetate to prevent an increase in viscosity, and finally a 24.2% by weight ethyl acetate solution was obtained. The slow volatile residual monomer in the adhesive solution thus obtained is 2-ethylhexyl acrylate.
It was 1.8% by weight. In addition, the easily volatile residual monomer is
n-butyl acrylate was 3.4% by weight. Next, a therapeutic adhesive sheet was prepared in the same manner as in Example 1, and further tested in the same manner as in Example 1 for drug extraction properties, adhesive strength, and practical skin adhesion. The results are shown in the Comparative Example 1 column of Table 1. Comparative example 2 2-ethylhexyl acrylate
64.4g (0.35mol) n-butyl acrylate 101.1g (0.79mol) Methacrylic acid 5.2g (0.06mol) Ethyl acetate 60g To the mixture of the above components, add 0.8g of azobisisobutyronitrile as a polymerization catalyst to 100ml. The ethyl acetate solution was added to the polymerization reaction in 10 batches, and the polymerization was carried out at 60°C for 40 hours under a nitrogen stream. During this time, stirring was continued while adding ethyl acetate to prevent an increase in viscosity, and finally a 23.5% by weight ethyl acetate solution was obtained. The slow volatile residual monomer in the adhesive solution thus obtained is 2-ethylhexyl acrylate.
It was 1.3% by weight. Furthermore, n-butyl acrylate, which is an easily volatile residual monomer, was 2.9% by weight. Comparative example 3 2-ethylhexyl methacrylate
69.3g (0.35mol) n-butyl acrylate 108.8g (0.85mol) 1,6-hexane glycol dimethacrylate
0.046 g (0.015 mol%) Ethyl acetate 60 g A solution of 0.6 g of azobisisobutyronitrile in 100 ml of ethyl acetate was added to the mixture of the above components in 5 portions during the polymerization reaction, and the mixture was heated at 65°C under a nitrogen stream. at 30
Polymerized over time. During this time, stirring was continued while adding ethyl acetate to prevent an increase in viscosity, and finally a 25.6% by weight ethyl acetate solution was obtained. The slow volatile residual monomer in the resulting adhesive solution was 0.44% by weight of 2-ethylhexyl methacrylate. Further, the amount of n-butyl acrylate, which is an easily volatile monomer, was 1.4% by weight. This adhesive is 2-ethylhexyl methacrylate versus n-
The ratio of butyl acrylate was 29:71, but the average carbon number of the methacrylic acid alkyl ester was as high as 8. Next, in the same manner as in Example 1, drug extraction properties, adhesive strength tests, and practical skin adhesion tests were conducted. The results are shown in the Comparative Example 3 column of Table 1.

[Table] Yes.

Claims (1)

[Claims] 1. A therapeutic adhesive tape or sheet in which a base material is provided with a pressure-sensitive adhesive layer containing a drug, in which the pressure-sensitive adhesive is a copolymer of an alkyl methacrylate and an alkyl acrylate. , the amount of components involved in the copolymer of methacrylic acid alkyl ester and acrylic acid alkyl ester is in the range of 40:60 to 15:85 in molar ratio, and the total amount of methacrylic acid alkyl ester and acrylic acid alkyl ester in the copolymer is The average number of carbon atoms in the alkyl group of methacrylic acid alkyl ester is 3 to 5, the average carbon number of the alkyl group in methacrylic acid alkyl ester is 6 or less, and the average carbon number of the alkyl group in acrylic acid alkyl ester is 4 or less; A therapeutic adhesive tape or sheet, characterized in that the amount of residual monomers of a methacrylic acid alkyl ester having 4 or more alkyl groups and an acrylic acid alkyl ester having 5 or more carbon atoms is 0.2% by weight or less.