JPH0259124B2 - - Google Patents

Description

[Detailed description of the invention]

B. Industrial Application Field The present invention relates to oral sustained release preparations. More specifically, sustained oral release, which is characterized by being suspended in the stomach and gradually releasing the drug after oral administration, thus supplying the drug at a concentration sufficient to have a therapeutic effect over a long period of time. Regarding formulations. B. Prior Art Conventionally, various proposals have been made regarding formulations and formulation methods for delaying the release of drugs from formulations and sustaining the efficacy of drugs for a long period of time. Among these, the following four examples are examples of attempts to maintain an effective blood concentration by releasing the drug over a long period of time while it remains in the stomach. That is, the method described in Japanese Patent Application Laid-open No. 49-61323 is as follows:
The core of the drug is coated with a polymer film that swells in gastric fluid, and its mechanical size prevents it from passing through the pylorus and extends its residence time in the stomach. The method described in the publication uses a large amount of a fatty substance with a low specific gravity, suspending it in gastric juice, and releasing the drug through the formed hydrogel membrane. In both of these methods, the drug is released by forming a single body in the stomach (here, a "single body" refers to one individual as opposed to a dispersion of many granules). Due to physiological factors (diet, stress, medical conditions) or external factors, there is a possibility that the drug may move to the intestinal tract before its release is completed. The method described in JP-A-50-121418 is to coat a hollow material such as expanded polystyrene, hard gelatin capsules, or foamed shells with a gastric fluid-resistant film, and then coat the drug with a drug to float it in the gastric fluid.
Although it is intended to be retained therein, it still has drawbacks such as being a single body and requiring a complicated manufacturing method. The method described in JP-A No. 52-76418 involves coating a blowing agent mainly consisting of bicarbonate with a coating agent containing a drug, or coating a mixture of a blowing agent and a drug with a conventional coating agent. By doing so, the drug is suspended in the gastric fluid and is intended to be released gradually, but it has drawbacks such as an insufficient sustained drug release effect. On the other hand, JP-A-54-41320 and JP-A-55-118414 disclose sustained release preparations consisting of a mixture of cellulose lower alkyl ether and polyacrylic acid or a pharmaceutically acceptable salt thereof. It is stated that by changing the ratio of cellulose lower alkyl ether to polyacrylic acid or a pharmaceutically acceptable salt thereof, it is possible to control the release rate of the drug according to the therapeutic purpose. . However, its application site is mainly in the oral cavity, and no study has been conducted as an oral preparation. C. Purpose of the Invention The present inventors, unlike these prior art,
Concerning formulation composition to treat gastric local diseases and systemic diseases for which sustained release is expected to increase efficacy by dispersing and retaining the drug in the stomach and sustaining drug release from the drug. As a result of extensive research, we surprisingly found that when a formulation consisting of a mixture containing cellulose lower alkyl ether, polyacrylic acid or its pharmaceutically acceptable salt, a blowing agent, and a drug was orally administered, fine granules In the case of tablets as well as granules, they remain suspended in the stomach in a substantially dispersed form as granules, gradually releasing the drug, and such preparations exhibit oral sustained release. We have discovered that it is extremely excellent as a formulation, and have arrived at the present invention. D. Constitution of the Invention The present invention provides cellulose lower alkyl ether,
It is an oral sustained release formulation consisting of a mixture containing polyacrylic acid or a pharmaceutically acceptable salt thereof, an effervescent agent, and a drug. The cellulose lower alkyl ether used in the present invention is one in which a plurality of hydroxyl groups of cellulose are at least partially substituted with the same or different lower alkyl ether groups. The lower alkyl group of the lower alkyl ether group may be substituted with a substituent. Preferred examples of such substituents include hydroxyl groups. Preferred examples of the optionally substituted lower alkyl group include a methyl group and a hydroxy lower alkyl group having 3 to 8 carbon atoms. Examples of the cellulose lower alkyl ether include methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose. Among these, hydroxypropylcellulose, hydroxyethylcellulose, or hydroxypropylmethylcellulose has an excellent sustained release effect in gastric juice when mixed with polyacrylic acid or a pharmaceutically acceptable salt thereof and a blowing agent. From this point of view, it is preferable. Among them, it is more preferable to use hydroxypropylcellulose. Hydroxypropylcellulose can be used with any molecular weight, but the viscosity of a 2% aqueous solution at 20°C is 3~3.
10000 centipoise, more preferably 1000-4000
It is even more preferable to use centipoise. The polyacrylic acid or its pharmaceutically acceptable salt used in the present invention is desirably determined by shape retention and drug sustained release properties when formed into a mixture with cellulose lower alkyl ether and a blowing agent. is an aqueous solution of the sodium salt of polyacrylic acid with a concentration of 0.2% as polyacrylic acid and a pH of 7 to 7.5 at 25.0±0.5℃.
Those exhibiting a viscosity of 200 to 200,000 centipoise when measured at 1 are preferably used. The polyacrylic acid referred to in the present invention includes not only polyacrylic acid alone, but also polyacrylic acid containing a small amount (usually 20
Those containing other water-soluble polymers (up to % by weight) may also be used. Furthermore, polyacrylic acid refers not only to polyacrylic acid homopolymers, but also to copolymers obtained by copolymerizing methacrylic acid, styrene, vinyl ether monomers, etc. with acrylic acid. Naturally, this copolymerization ratio should be limited to a copolymerization ratio that can achieve the object of the present invention. Furthermore, the pharmaceutically acceptable salts of polyacrylic acid as used in the present invention include sodium salts, potassium salts, and the like. The blowing agent used in the present invention is a carbonate or bicarbonate such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, potassium hydrogen carbonate, etc. Alternatively, a mixture of these salts and an organic acid such as citric acid, tartaric acid, succinic acid, fumaric acid, maleic acid, or asmarbic acid may be used. In order to further increase the dispersibility of the mixture of cellulose lower alkyl ether and polyacrylic acid or its pharmaceutically acceptable salt by foaming and foaming,
Or when targeting patients with achlorhydria,
It is preferable to use carbonate or bicarbonate in combination with an organic acid such as citric acid, tartaric acid, succinic acid, fumaric acid, maleic acid, or ascorbic acid. The ratio of cellulose lower alkyl ether, polyacrylic acid or a pharmaceutically acceptable salt thereof, and blowing agent contained in the formulation is determined by the sustained release of the mixture of cellulose lower alkyl ether and polyacrylic acid or its pharmaceutically acceptable salt. effect and dispersion effect of blowing agent,
Depending on the floating effect, 0.1 to 1000 parts by weight of polyacrylic acid or a pharmaceutically acceptable salt thereof, cellulose lower alkyl ether and polyacrylic acid or a pharmaceutically acceptable salt thereof per 10 parts by weight of cellulose lower alkyl ether. Preferably, the blowing agent is used in an amount of 1 to 40 parts by weight per 10 parts by weight of the mixture of salts acceptable to the above. More preferably, the amount is 0.1 to 10 parts by weight of polyacrylic acid or a pharmaceutically acceptable salt thereof per 10 parts by weight of cellulose lower alkyl ether. More preferably, the blowing agent is used in an amount of 1 to 10 parts by weight per 10 parts by weight of the mixture of cellulose lower alkyl ether and polyacrylic acid or a pharmaceutically acceptable salt thereof. The active ingredient included in the present invention may be any drug for treating gastric diseases or systemic diseases for which the therapeutic effect is expected to be further increased than in the past through sustained release. Examples include: Gastrointestinal drugs (allantoin, aldioxa, alcloxa, pirenzepine hydrochloride, secretin, urogastrone, cetraxate, cimetidine, ranitidine, p-(trales-4-aminomethylcyclohexylcarbonyl)phenylpropionate hydrochloride, brostaglandins, etc.) Peptic ulcer treatment: synthetic aluminum silicate, natural aluminum silicate, dimagnesium aluminate silicate, bismuth magnesium aluminate silicate, dry aluminum hydroxide gel, hydrotalcite, magnesium aluminate metasilicate, magnesium silicate, magnesium oxide , heavy magnesium oxide, magnesium hydroxide, magnesium carbonate, precipitated calcium carbonate, and other antacids; sucrose sulfate, hebstatin, strebtostatin, and other anti-pepsin drugs; pepsin, diastase, lipase, and other anti-inflammatory enzymes) Neurological drugs (hypnotic sedatives such as diazebam and estazolam; anticonvulsants such as phenytoin, meprobamate, and nitrazepam; acetaminophen, ethenzamide, salicylamide, pentazocine, clofezone, indomethacin, ketobrofen, naproxen, flupiprofen, diclofenac, clidanac,
Antipyretic, analgesic and anti-inflammatory agents such as corticosteroids, including alcrofenac, flufenamic acid, mefenamic acid, sulindac, piroxicam, menthol, camphor, D-penicillamine, dexamethasone, triamcinolone, betamethasone and prednisolone; neuropsychiatric agents such as chlorbromazine Medications: anti-vertigo drugs such as isoprenaline, petahistine mesylate, scopolamine; general anesthetics, etc.) Allergy drugs or antihistamines (diphenhydramine, periactin, etc.), cardiovascular drugs (cardiac drugs such as digitalis, ubidecarenone; pindolol, β-blockers or antiarrhythmic agents such as propranolol hydrochloride, albrenolol hydrochloride, oxprenolol hydrochloride; theophylline, trichlormethiazide, spironolactone, methyclothiazide,
Diuretics such as metolazone, tripamide, furosemide, penfluzide; antihypertensive agents such as dihydropyridine derivatives including reserpine, clonidine hydrochloride, methyldova, hydralazine, syrosingobine, recinamine, cinnarizine, brazosin hydrochloride, nifedipine; vascular reinforcing agents such as rutin, carbazochrome; Vasoconstrictors such as dihydroergotamine mesylate, dihydroergotoxine mesylate; coronary vasodilators such as nitroglycerin, isosorbitol nitrate, dilazeb hydrochloride, nifedipine, diltiazem hydrochloride, trimetazidine hydrochloride, trapidil, dipyridamole; inositol hexanicotinate, etc. Peripheral vasodilators; arteriosclerotic agents such as clofiplate; pentoxifylline, cytochrome C, dextran sodium sulfate, pyrithioxine,
Citicoline, nicardipine hydrochloride, dopamine hydrochloride, prostaglandins, prostacyclin, doptamine hydrochloride, albrostadil, ifenbrodil tartrate, etc.), respiratory agents (antitussive expectorants such as efuedrine, codeine, bromhexine; isobroterenol, dextro metorphan, orsibrenaline, ibratrobium bromide, cromoglycic acid, etc.); hormones or antihormones (human growth hormone, corticothrobin, oxytocin, pasobrecin, protirelin tartrate, and other pituitary gland hormones; androgenic hormones, such as testosterone) agents; female hormones such as brogesterone and estradiol; salivary gland hormones, thyroid and parathyroid hormones, anabolic steroids, adrenal hormones, etc.) Urogenital drugs (such as uterotonic agents such as dinoprost and dinoprostone), metabolic drugs (alfacalcidol, 1.24
- Vitamins such as dihydroxycholecalciferol and mecobalamin; nutritional tonic alterants; glutathione, ATP, aprotiline, gapexate mesylate, etc.), tumor drugs (krestin, ancitabine, mitomin, methotrexate, carbocone, cytarabine, picibanil, tegafur) 5-fluorouracil derivatives including carmofur, 5
-fluoro-2'-deoxyuridine and its derivatives), antibiotics (tetracycline antibiotics, penicillin antibiotics, cephalosporin antibiotics, etc.) chemotherapeutic agents (clotrimazole, pyrrolnitrine, alaphosphalin, sulfur drugs, etc.) ), the amount of such drug is appropriately determined depending on the strength of activity of each drug. The oral sustained release preparation of the present invention includes fine granules, granules,
Preferably, it is in the form of tablets, fine granules, granules, or capsules filled with tablets. The oral sustained release preparations of the present invention are not only in the form of fine granules or granules, but also in the case of capsules, when the capsule is dissolved by gastric juice, and when the mixture encounters gastric juice, the tablets immediately effervesce. Cellulose lower alkyl ether and polyacrylic acid or their pharmaceuticals are dispersed in granules, and the foaming agent present in the granules gradually reacts with gastric juice, causing carbon dioxide bubbles to float and prolong the residence time in the stomach. further enhances the sustained release function of salts that are acceptable to the public. Moreover, since the preparation of the present invention is in the form of many particles in the stomach, it moves to the intestinal tract before the release of the drug is completed, which can often happen with a single drug. Compared to conventional sustained-release drugs that remain in the stomach without fully achieving the purpose of sustained release, even if some of the particles move to the intestinal tract, most of the particles that remain and float This also has the advantage of being able to maintain sustained release properties, thereby reducing individual differences in drug efficacy. The oral sustained release preparation provided by the present invention with excellent gastric retention is produced as follows. That is, first, a foaming agent powder, cellulose lower alkyl ether, polyacrylic acid or a pharmaceutically acceptable salt thereof, and a drug for treating gastric diseases and systemic diseases whose therapeutic effects are expected to be further increased by sustained release are uniformly mixed together. After mixing, lubricants and excipients may be added as necessary to form dry granules using a conventional method, and the granules may be used as they are, or may be made into hard capsules or as needed for convenience of administration. Furthermore, a lubricant may be added and tablets may be prepared by a conventional method. Another manufacturing method is to uniformly mix cellulose lower alkyl ether, polyacrylic acid or a pharmaceutically acceptable salt thereof, and a drug, and then add one or two lubricants, binders, and excipients as necessary. The seeds and more are mixed thoroughly and made into dry granules according to a conventional method, and if necessary, the particle size is made uniform by classification. On the other hand, the foaming agent may be used alone or, if necessary, a lubricant, a binder, and an excipient may be added thereto to form dry granules. These two types of granules may be mixed together and used as granules or fine granules, or they may be filled into hard capsules for convenience of administration, or a lubricant may be added as needed to make a regular granule. Depending on the method, it may also be made into tablets. Examples of lubricants used here, if necessary, include talc, stearic acid and its salts, waxes, etc., and examples of binders include starch, dextrin, tragacanth, gelatin, polyvinylpyrrolidone, polyvinyl alcohol, etc. However, as excipients, starch,
Examples include crystalline cellulose, dextrin, lactose, mannitol, sorbitol, anhydrous calcium phosphate, and the like. When using a drug that becomes unstable when it comes into contact with polyacrylic acid, bicarbonate used as a blowing agent, or organic acid, the drug must be injected in advance into a well-known gastrointestinal solution such as hydroxypropyl methylcellulose or polyvinyl acetal diethylaminoacetate. After being coated with a soluble coating agent or granulated with known excipients such as starch and lactose that are inert to drugs,
The composition of the present invention may be used as tablets, granules, or fine granules. E. Effects of the Invention The effects and characteristics of the preparation provided by the present invention as described above are as follows: 1. It remains suspended in the stomach for a long time, and therefore the drug can act directly and locally at high concentration on the stomach. The drug itself does not pass through the absorption or action site of the drug. 2. After absorbing gastric juice and dispersing into particles, they swell and gradually release the drug. That is, foaming occurs due to the acidity of gastric fluid, and the mixture of cellulose lower alkyl ether, polyacrylic acid or its pharmaceutically acceptable salt, and drug is first dispersed in granular form, and then swelling occurs gradually, and the drug is released from the swollen portion. This allows the drug to continue to be delivered to the site of application or absorption over a long period of time. 3 Even if taken in the form of a capsule or tablet, it becomes a granular dispersion in the stomach, so the entire amount of unreleased drug moves into the intestinal tract before the release of the drug, which can occur in a single drug, is completed. Possibilities can be prevented. 4. By varying the ratio of cellulose lower alkyl ether to polyacrylic acid or a pharmaceutically acceptable salt thereof, it is possible to control the release rate of the drug to meet therapeutic objectives. 5. The manufacturing method is easy, and the molding is performed by pressure molding and dry grinding, so the stability of the drug is not impaired, and it is also advantageous from an economical point of view. F. EXAMPLES The present invention will be explained in detail with reference to Examples below, but the present invention is not limited by these in any way. Experimental Example 1 The following experiment revealed that the drug was gradually released from the formulation of the present invention. 5 parts by weight of riboflavin was added to 95 parts by weight of a mixture of hydroxypropyl cellulose and polyacrylic acid in different ratios, and granules having a size of 12 to 24 meshes were prepared by a dry method. On the other hand, for 70 parts by weight of a mixture of hydroxypropylcellulose and polyacrylic acid in different proportions, 5 parts by weight of riboflavin, sodium hydrogen carbonate
25 parts by weight was added to form granules of 12 to 24 mesh by dry method. Further, 5 parts by weight of riboflavin was added to 95 parts by weight of hydroxypropyl cellulose or lactose, and granules of 12 to 24 meshes were prepared by a dry method. On the other hand, 25 parts by weight of sodium hydrogen carbonate and 5 parts by weight of riboflavin were added to 70 parts by weight of hydroxypropyl cellulose or lactose, and by dry method
It was made into granules of 12 to 24 mesh. A riboflavin dissolution test was conducted on 200 mg of these in granular form according to the Japanese Pharmacopoeia dissolution test method. The dissolution test is the second method, the test solution is 500ml of the first solution,
I did it at 100 revolutions. The results are shown in Table-1 and Table-2.

【table】

[Table] Tables 1 and 2 show that the mixture of hydroxypropylcellulose and polyacrylic acid exhibits sustained release properties, and that the elution time varies depending on the mixing ratio. Furthermore, it can be seen that when sodium hydrogen carbonate is further included, the granular preparation is dispersed and floats, and the elution time is further extended. still,
No floating was observed in the granular formulation that did not contain a blowing agent. Example 1 85 parts by weight of hydroxypropyl cellulose (20°C, viscosity of 2% aqueous solution is 2080 centipoise), 15 parts by weight of polyacrylic acid (viscosity of 0.2% aqueous solution at 25°C, pH 7.3 is 11500 centipoise), pigment ( Acoranth) and 50 parts by weight of sodium hydrogen carbonate were uniformly mixed and made into granules having a particle size in the range of 20 to 24 meshes (0.70 mm to 0.84 mm) by a dry method. Fill 150mg of this granule into a No. 2 capsule,
Japanese Pharmacopoeia dissolution tester (method 2, 1st liquid 500ml,
100 rpm), it was confirmed that after the capsule film dissolved and disappeared in about 10 minutes, the granules contained were dispersed and suspended on the surface of the test liquid, and that they remained dispersed and suspended in the same way 12 hours later. . Eight hours after administration of the 10 granules prepared above into mini-hard gelatin capsules, the abdomen was opened to the rats, and it was confirmed that the pigment (amaranth) remained, indicating that the granules had no gastric retention property. It was shown to be long. Experimental Example 2 85 parts by weight of hydroxypropyl cellulose (viscosity of 2% aqueous solution at 20°C, 2080 centipoise) and 15 parts by weight of polyacrylic acid (viscosity of 0.2% aqueous solution at 25°C, pH 7.3 is 11500 centipoise) were uniformly added. Add a predetermined amount of sodium bicarbonate powder to the mixed powder, mix uniformly, and form granules in the range of 12 to 24 mesh by dry method. Fill 150 mg of this granule into hard capsules, and test using a Japanese Pharmacopoeia dissolution tester (No. 2). law,
Dispersion and floating conditions were examined using the first solution (500 ml, 100 rpm) up to 4 hours. The results are shown in Table 3.

[Table] As is clear from Table 3, when sodium hydrogen carbonate is used as a blowing agent, dispersion and floating properties are suitable. Example 2 70 parts by weight of hydroxypropyl cellulose (viscosity of 2% aqueous solution at 20°C, 2080 centipoise), 30 parts by weight of polyacrylic acid (viscosity of 11500 centipoise, 0.2% aqueous solution at 25°C, pH 7.3), and pigment ( 2 parts by weight of amaranth) were mixed uniformly and made into granules with a particle size of 12 to 24 meshes (0.71 mm to 1.41 mm) by a dry method (granules [A]).
Add 40 parts by weight, mix uniformly, and use a dry method to make 16
It was made into a granular material of ~24 meshes (0.71 mm to 1.00 mm) (granular material [B]). 70 parts by weight of granules [A], 30 parts by weight of granules [B] and 0.5 parts by weight of magnesium stearate were uniformly mixed, and the mixture had a diameter of 10 mm, a thickness of 3 mm, and a weight of 200.
mg tablet. When this tablet was observed using the Japanese Pharmacopoeia dissolution tester in the same manner as in Example 1, it was found that the tablet foamed and disintegrated immediately after being added to the test solution, and was dispersed and suspended in granular form, and that it remained suspended and dispersed even after 8 hours. confirmed. Example 3 Methylcellulose (viscosity of 2% aqueous solution at 20℃
The viscosity of a 0.2% aqueous solution of 80 parts by weight of polyacrylic acid (25°C, pH 7.3) is
11500 centipoise) and 40 parts by weight of sodium bicarbonate and isoproterenol hydrochloride.
20 parts by weight were mixed uniformly. Add 0.8 parts by weight of magnesium stearate, diameter 10mmφ, hardness 4~
The tablets were made into 5 kg tablets, and the tablets were roughly crushed to make granules with a size ranging from 12 to 24 meshes, and 150 mg of the granules were filled into No. 2 capsules. This capsule was subjected to a dissolution test using the Japanese Pharmacopoeia dissolution test method (method 2, 500 ml of liquid, 150 rpm). After the capsule film dissolved and disappeared in about 10 minutes, it was immediately dispersed on the surface of the test solution, and remained as a granular material for up to 12 hours. It was observed that the 50% elution time was 3.2 hours and the 80% elution time was 7.8 hours.
Good sustained release properties were demonstrated. Example 4 Hydroxypropyl methylcellulose (20°C,
60 parts by weight of 2% aqueous solution (viscosity 14.3 centipoise) and 0.2% polyacrylic acid (25°C, pH 7.3)
40 parts by weight of the aqueous solution (viscosity of 11.500 centipoise) and 20 parts of tetracycline hydrochloride are mixed uniformly,
Add 0.6 parts of magnesium stearate, 10 dia.
The tablets were made into tablets having a diameter of mmφ and a hardness of 3 to 4 kg, and the tablets were coarsely crushed using a crusher, and granules of 12 to 24 meshes were obtained using a classifier. (Particulate matter [A]). Separately, 30 parts of tartaric acid was added to 70 parts of sodium bicarbonate and mixed uniformly. Furthermore, 0.5 part of magnesium stearate was mixed to form tablets with a diameter of 10 mmφ and a hardness of 3 to 4 kg. They were roughly crushed and classified into 12 to 24 mesh tablets. Granules were obtained.
(Particulate matter [B]). 60 parts by weight of granules [A], 40 parts by weight of granules [B] and 0.5 parts by weight of magnesium stearate were mixed uniformly, 200 mg of this was filled into No. 2 capsules, and a dissolution test was conducted in the same manner as in Example 3. After aging, it was observed that the sample was dispersed and suspended on the surface of the test solution until the 8th hour, and the 50% elution time was 2.5 hours.
The 80% dissolution time was 6.5 hours, indicating good sustained release properties.

Claims (1)

[Scope of Claims] 1. An oral sustained release preparation comprising a mixture containing cellulose lower alkyl ether, polyacrylic acid or a pharmaceutically acceptable salt thereof, an effervescent agent, and a drug. 2 0.1 to 1000 parts by weight of polyacrylic acid or a pharmaceutically acceptable salt thereof based on 10 parts by weight of cellulose lower alkyl ether, a mixture of cellulose lower alkyl ether and polyacrylic acid or a pharmaceutically acceptable salt thereof 10 2. The oral sustained release preparation according to claim 1, which contains the blowing agent at a ratio of 1 to 40 parts by weight. 3. The oral sustained release preparation according to claim 1 or 2, wherein the effervescent agent is a carbonate, a bicarbonate, or a mixture of a carbonate or bicarbonate and an organic acid. 4. The oral sustained release preparation according to any one of claims 1 to 3, which is in the form of fine granules, granules, capsules, or tablets. 5. The oral sustained release preparation according to any one of claims 1 to 4, wherein the cellulose lower alkyl ether is hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, or ethylcellulose. 6 Cellulose lower alkyl ether is hydroxypropyl cellulose, and 2 at 20°C
5. The sustained release preparation according to any one of claims 1 to 5, which exhibits a viscosity of 3 to 10,000 centipoise in an aqueous solution. 7 Polyacrylic acid has a viscosity of 200 to 200,000 centipoise when measured at 25.0 ± 0.5°C in an aqueous solution of its sodium salt with a concentration of 0.2% as polyacrylic acid and a pH of 7.0 to 7.5. The oral sustained release product according to any one of claims 1 to 6, which is a product.