SE459845B - ORAL COMPOSITION FOR GINGIVIT TREATMENT - Google Patents

Description

459 845 dental disease. Organisms such as anaerobic neighboring organisms are generally present in the removed product as well as in the tissue involved and can be absorbed into the body via the lymph vessels or the venous blood. The course of the pyoretic process usually begins with gingivitis, which begins at the edges of the gums, after which the gums become increasingly tender and sensitive and appear flabby, inflamed and swollen. Periodontal pockets appear and an infection occurs in the pockets.

Effective control and prevention of gingivitis is therefore a desire to prevent persistent periodontal disease.

A large number of different agents have previously been proposed and used to control oral diseases and ailments such as plaque, salivary glands, tartar, tartar, caries, bad breath and periodontal diseases such as gingivitis and pyorrhea, but none of them have been completely satisfactory. Oral compositions, which contain anti-inflammatory agents which reduce the symptoms of swelling, bleeding and inflammation associated with gingivitis by preventing the formation of tartar and / or counteracting tartar, include, for example, an imidazole such as histadine or histamine, such as - written in US 3,497,591; a dichloro-2-guanidinobenzimidazole as described in US 3,523,154; carrageenan as described in US 4,029,760; a mixture of tranexamic acid and folic acid as described in US 4,272,512; and tannic acid as described in US 4,273,758. All said agents are non-antimicrobial.

Furthermore, US 3,577,520 discloses a toothpaste composition containing 5,5-diaryl-2,4-imidazolidinediones for the treatment of pyorrhea by curing pathological changes caused by periodontitis.

US 3,911,133 discloses an antibacterial composition which is effective against both gram-positive and gram-negative bacteria and which comprises an imidazole derivative, which is a bis (imidazolium quaternary salt), useful in mouthwash, toothpaste and dental gels as an agent. to counteract the formation of dental plaque or to prevent gingivitis.

US 4,243,670 discloses imidazolium derivatives having potent antimicrobial activity against dermatophytes, yeasts, molds, biphasic fungi and gram-positive cocci; and useful as an additive in oral hygiene products such as toothpaste and mouthwash, to avoid microbial infections in the oral mucosa and as a prophylactic against infection.

It is also known to those skilled in the art that certain gram-negative organisms, such as Bacteroides asaccharolyticus or Bacteroides gingivalis, are associated with adult periodontal F-tit. By removing these and other gram-negative anaerobes from the plaque deposited on the gum tissue, periodontal diseases can be effectively controlled and prevented.

Thus, Listgarton et al. and J. Periodont. Res. Ig: 65-75 (1979) showed that metronidazole 459,845 ïH 2 CH 2 OH g when applied to the body system causes the said gram-negative anaerobes to be removed from the plaque. This was confirmed.by Heijl and Lindhe in J.

NO 3 Clinical Periodontology Q, 197 - 209 (1979), which states that metronidazole effectively reduces the causes of plaque and gingivitis in dogs; and by Loesche et al. in J. of Clinical Periodontology, §, 29 - 44 (1981), which states that metronidazole effectively reduced the amount of anaerobic B. asaccharolyticus in plaques removed from periodontal pockets, which was accompanied by a marked decrease in pocket depth and a considerable improvement in retention.

Metronidazole, which is sold under the trademark Flagyl (: Å) is carcinogenic (Physician Reference Handbook, p. 1761) and can not be used arbitrarily.

It has now been found that another imidazole derivative is effective against the said gram-negative anaerobic organisms, which is non-mutagenic and non-carcinogenic and can be applied topically to the oral cavity for the treatment of gingivitis, namely l-imidazoy1-1- (p-chlorophenoxy) -3, 3-dimethyl-2-butanone.

The imidazoyl ketones, such as 1-imidazoyl-1- (4-chlorophenoxy-3,3-dimethyl-2-butanone, are described in US 3,812,142 and US 3,903,287 as an antifungal agent useful in pharmaceutical compositions such as pastes , gels, creams and aqueous or non-aqueous suspensions 459 845. Its action against pathogenic protozoa, gram-positive and gram-negative bacteria such as Staphylococci and Escherichia coli is also mentioned therein.

British Patent Specification 1,502,144 and its German equivalent in Patent No. 2,430,039 relate to compositions for treating hair and skin which are effective against Pityrosporum ovale and contain the antifungal imidazoyl ketones dispersed in a dermatologically acceptable carrier containing a active detergent compound. The compositions are in the form of creams, aerosols, powders and liquids. German Pat. -in-oil or oil-in-water emulsion or a spray liquid, useful for protecting coatings of mortar, paint dispersions, wallpaper, tiled surfaces, paints, adhesives, asphalt, furniture, leather, shower curtains, textiles, foodstuffs dry, wood and paper against a wide range of pathogenic fungi, molds and bacteria. However, no mention is made of Bacteroides asaccharolyticus or gingivalis, the special anaerobic gram-negative organisms found in gingivitis. German Pat. No. 2,700,806 also relates to a mixture of the imidazoyl ketone fungicide and a quaternary ammonium bactericide which is useful in protecting materials such as paints, adhesives, asphalt, cellulose, paper, textiles, leather and wood. Although the prior art relates to the said imidazoyl ketone in the form of an antifungal agent and its use in pharmaceutical compositions, especially in compositions for the treatment of the skin and skin, there is no description as to its use in dental compositions or its action against the specific gram-negative anaerobic organisms associated with gingivitis and periodontitis.

It has now been found that the water-insoluble imidazoyl ketone 1-imidazoyl-1-dimethyl-2 (p-chlorophenoxy) -3,3-butanone is selectively active against the particular anaerobic gram-negative organisms associated with gingivitis when it applied topically to the affected gums. Thus, a primary object of the present invention is to provide an oral composition which contains the said water-insoluble imidazoyl ketone as an anti-gingival agent, solubilized in an oral vehicle.

Another object of the invention is to provide a mouthwash or toothpaste with effective effect in preventing and treating plaque, gingivitis and periodontitis.

A further object of the invention is to provide an oral composition comprising said anti-gingivitant solubilized in an aqueous vehicle containing a nonionic active compound.

Another object of the invention is to provide an oral composition comprising the antibacterial agent which is useful in the prevention and treatment of gingivitis in animals. 459 845 Other objects and advantages and novel features of the invention will be apparent in part from the following description, and in part will be apparent to those skilled in the art upon reading the same, or from practice in the practice of the invention.

The objects and advantages of the invention may be realized and attained by the means and combinations set forth in the appended claims.

Thus, in order to achieve the said and other objects in accordance with the present invention, as embodied herein and broadly described herein, the invention thus relates to an oral composition according to claim 1. Embodiments of the invention are set out in claims 2 to 5. .

The oral vehicle may be in liquid form such as a mouthwash or rinse aid, solid form such as chewing gum or tooth powder, paste or cream form such as a toothpaste or toothpaste. These oral compositions are non-toxic and have a p fl of about 5 - 7.5.

The typical surfactant contains at least -80% by weight of hydrophilic units of the polyoxyene and the hydrophobic group which preferably have a molecular weight of about 3250, as in the mixed polymers of propylene oxide and ethylene oxide. The ratio of solubilizing agent to the imidazole compound is 3: 1 to 25: 1. At conditions above 25: 1 gel formation occurs. The antiging agent used in the present invention is 1-imidazoyl-1- (p-chlorophenoxy) -3,3-dimethyl-2-butanone having the structural formula: c1 - [- \ -o-cH-coc ( cu3) 3 ¶¶ and is prepared by reacting 1-bromo-1- (4-chlorophenoxy) -3,3-dimethyl-2-butanone with imidazole dissolved in acetonitrile, as described in US 3,812,142 and 3,903,287 which are included as part of this description.

This imidazoyl ketone is a water-insoluble crystalline powder, m.p. 94.5 DEG-97.80 DEG C., which can be obtained from the Bayer Company as Climbazole. Due to the insolubility in water of this imidazole compound, it must first be solubilized in a nonionic compound before the addition of ionic materials in an aqueous medium.

It has unexpectedly been found that when this antibacterial compound is added to oral vehicles, it not only acts against the particular anaerobic organisms which cause periodontal diseases, but it also markedly relieves the disease when applied topically and reduces the symptoms of gingivitis associated with periodontitis. The minimum inhibitory concentration (MIG) required to kill Bacteroides assaccharolyticus (Forsyth strain}, as determined by the procedure of Walker et al. (Antimicrobial and ZS Chemotherapy. Vol. 16, pp. 452-457, 1979) is between 7.8 and 31.2 fmg per ml The MIC value of B. gingivalis 459 845 is 25 kg per ml The MIC value of B. gracilis and Fusobacterium, other gram-negative organisms, is higher than 50 for each; The value of the gram-positive organism Actinomyces viscosus is 125 for the aerobic strain and 250 for the anaerobic strain, which clearly shows the selective antibacterial effect of the specific imidazole compound used here as an antiging agent.

An evaluation of oral anti-gingivitis compositions using a mouthwash containing 0.3% Climbazole, in an experiment performed on 30 beagle dogs for 10 weeks, clearly shows its superior effect against gingivitis. In the procedure used, hard and soft tooth deposits were completely removed, after which the dogs were kept on a soft diet for six weeks to allow the formation of gingivitis. The teeth were then treated with the experimental solutions twice a day, 5 days a week, for about 15 seconds on each side of the mouth. The animals were examined and the degree of inflammation in the gums was noted according to a scale from 0 to 3. O = no inflammation. l = slight local edema and redness at the edge of the gums, no bleeding with gentle pressure with the finger. 2 = moderate edema and redness in the edge of the gums and bleeding with gentle pressure with the finger. 3 = severe edema and ulceration in the edges of the gums and adjacent gums as well as bleeding even without gentle finger pressure. A placebo rinse and a rinse containing 0.5% metronidazole were used as negative and positive control, respectively. The results are summarized in Table l. 459 845 m fl onmnë flfl u æ m_o NN wßm 1 HN mßm 1 1 mmm HH HH mßm _ 1 æm Nßm 1 m wßm HH Hmums fi HæHm. _ l fl oumw fi cohuwå wm ~ o NH w ~ m 1 Hm mmm 1 m mmm m H @ øws fi HæxmonwomHm NHHNHHNHQ m = H = m = HHu = ~ s @ n h0xO®> OH uO ¥ Ow> m Cm fi hß fl Gmhm KEÛÜfiflH H 45 45E 845 11 Compared with placebo, both metronidazole and Climbazole significantly reduced the development of the gingival unit 2. However, a smaller amount (0.3%) Climbazole has the same effect against gingivitis as larger amounts (0.5%) of metronidazole. . Although metronidazole, when administered to the body, is an effective remedy for the specific gram-negative microorganisms that cause periodontal disease, as has been extensively discussed in the prior art, it does not have as good an effect when - brought topically. The reason for the poor results is the absence in its structural formula of a suitable hydrophobic group, which is required for the penetration into the gum tissues. Climbazole, on the other hand, has a large hydrophobic group, (p-chlorophenoxy) -3,3-dimethyl-2-butanone, which provides good penetration into the tissues where the destructive periodontitis process takes place and which enables this antibacterial agent to maintain a concentration that effectively reduces the number of gram-negative anaerobic microorganisms associated with this disease. In addition, due to the nitro group, metronidazole is a mutagenic compound, whereas Climbazole has not been shown to be mutagenic in oral experiments due to the absence of a nitro group, as evidenced by the following structural formulas: 459 845 12 Climbazole Metronidazole ci (ca3) 3 clznz. cnz. The oral composition ~ of the invention may be in the form of a liquid, such as a mouthwash or a rinse aid. In these products, the vehicle typically consists of a water-alcohol mixture. In general, the weight ratio between water and alcohol is between about 1-1 n ... and about 20: 1, preferably between 3: 1 and 20: 1. The alcohol content is preferably about 20-40% by weight of the vehicle. The total amount of water-alcohol mixture in this type of composition is typically between about 70% and about 98% by weight of the composition. The pH of this liquid and other compositions of the invention is generally between about 5 and about 7.5.

An important component of the liquid oral compositions is about 1 to 5% by weight of a nonionic surfactant comprising 10 to 80% by weight of hydrophilic units of polyoxyethylene and also hydrophobic polyoxide propylene or higher fatty acid, fatty acid ester or fatty acid amide to solubilize it in water. insoluble Climbazole in the water-alcohol vehicle. Suitable nonionic surfactants are block polymers of ethylene oxide, mixed propylene oxide-ethylene oxide polymers polyoxyethylene-hexitan-mono-higher fatty acid esters having 459,845 13 to 20 carbon atoms in the higher fatty acid acyl group and, 4 to 10 10, preferably 10 to 80 moles of ethylene. . The hexitan is preferably sorbitan, although mannitan and other hexitanes are also useful, the higher fatty acid acyl group should have 10-16 or 20 carbon atoms, more preferably 12-16 or 18 carbon atoms and preferably about 12 carbon atoms, and the number of ethoxy groups should be 15 - 80, often preferably about 20.

Particularly suitable is a product from ICI, sold under the trademark Tween120, also known as Polysorbate 20, which consists of polyoxyethylene (20) sorbitan monolaurate.

Also useful are the products sold under similar designations, such as Tween 40, 60, 65 and 80, all of which are nonionic surfactants in which the higher fatty acid acyl group is palmitoyl, stearoyl or oleoyl and the number of moles of ethylene oxide per mole is about 20.

Of these materials, however, polyoxyethylene sorbitan monolaurate is generally preferred. Polyoxyethylene (80) sorbitan monolaurate can be used instead of Polysorbate 20.

Other suitable nonionic surfactants are the mono- and diethanolamides of higher fatty acids having about 10 to 18 carbon atoms in the acyl group, such as coconut monoethanolamide, coconut diethanolamide, lauric myristine diethanolamide, laurin monoethanolamide or combinations thereof.

The present oral compositions may have a substantially pasty form, such as a toothpaste or toothpaste. The vehicle in the pasty oral compositions contains polishes. Examples of polishes are water-insoluble sodium metaphosphate, potassium metaphosphate, tricalcium phosphate, calcium pyrophosphate, magnesium orthophosphate, trimagnesium phosphate, calcium carbonate, alumina, hydrated alumina, aluminosilicate. Zirconium silicates, silicic acid bentonite, crystalline silicic acid with particle sizes up to 5 microns, silicic acid gel, amorphous alkali metal aluminum silicate complex, hydrated alumina, dicalcium phosphate and mixtures thereof.

When visually clear gels are used, a colloidal silicic acid polish, such as those sold under the Syloid brand, such as Syloid 72 and Syloid 74, or under the Santocel brand, such as Santocel 100, and alkali metal aluminum silicate complexes, are particularly suitable because their refractive index is close. index for the gelling agent-liquid systems (including water and / or wetting agents) commonly used in toothpastes.

The polish is generally present in amounts varying between about 10% and about 99% by weight of the oral composition. Preferably it is present in an amount between about 10 and about 75% by weight of the toothpaste.

In a toothpaste, the liquid vehicle typically comprises water and a wetting agent in an amount of between about 10% and about 90% by weight of the composition. An important component of the toothpaste and toothpaste is about 20-40% by weight of a nonionic wetting agent comprising at least one wetting agent selected from the group consisting of polyethylene glycol and polypropylene glycol for solubilizing the water-insoluble Climbazole in the water vehicle.

Glycerol, sorbitol or mannitol can be used in the steel for part of the wetting agent, provided that the imidaxol compound is solubilized in the polyoxyethylene or polyoxypropylene glycol. A gelling agent, such as natural or synthetic gums or rubber-like materials, typically carrageenan, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, gum trace edge, polyvinylpyrrolidone, starch and hydroxypropylmethylcellulose, are generally present in an amount of 1% by weight of toothpaste. , preferably between about 0.5 and about%. A toothpaste or gel contains the liquids and solids in such proportions that they form a creamy or gelled mass which can be sprayed out of a pressure vessel or from a compressible tube of, for example, aluminum or lead.

The oral compositions of the invention may contain a non-soapy synthetic sufficiently water-soluble organic anionic or nonionic surfactant in concentrations generally between about 1 and 5% by weight, in order to improve the wetting and cleaning properties as well as the foaming properties.

US 4,041,149 lists suitable anionic surfactants in column 4, rows 31-38, and suitable nonionic surfactants in column 8, rows 30-68 and column 9, rows 1-12, which sections are hereby incorporated by reference.

The antibacterial oral compositions of the invention may optionally contain a fluorine-releasing compound, including inorganic fluoride salts such as soluble alkali metal salts, alkaline earth metal salts and heavy metal salts, for example, sodium fluoride, potassium fluoride, ammonium fluoride, calcium fluoride, calcium fluoride (I) fluoride, zinc fluoride, a tin fluoride such as stannous fluoride or stannous chlorofluoride, barium fluoride, sodium fluorosilicate, ammonium fluorosilicate, sodium fluorosirconate, sodium monofluorophosphate, aluminum monofluorophosphate and phosphorus monofluorophosphate. Alkali metal and tin fluorides, such as sodium and stannous fluorides, sodium monofluorophosphate and mixtures thereof, are preferred.

The amount of fluorine-releasing compound depends to some extent on the type of compound, its solubility and the type of oral composition, but it must be a non-toxic amount. In a solid oral composition, such as toothpaste or chewing gum, an amount of such a compound which releases at most about 1% by weight of the composition may be considered satisfactory. Any suitable minimum amount of the compound may be used, but preferably an amount sufficient to release about 0.005 to 1%, and preferably about 0.1% fluoride ions is used.

In the case of alkali metal fluorides and stannous fluoride, the component is present in a typical amount of up to about 2% by weight, based on the weight of the composition, and preferably between about 0.05 and 1%. In the case of sodium monofluorophosphate, the compound may be present in an amount of up to 7.6% by weight and more typically about 0.76%.

The oral compositions of the invention may contain many other various materials which do not adversely affect the properties of the composition, such as sweetening agents (eg saccharin, sucrose, lactose, maltose, sorbitol, etc.); aromatic oils (eg oils of mint, peppermint, evergreen, sassafras, cloves, sage, eucalyptus, marjoram, cinnamon, lemon, orange, etc.); dyes or bleaches (eg titanium dioxide); preservatives (eg sodium benzoate) and the like. Minor amounts, up to a total of about 5% by weight and preferably 0.01 to 3% by weight, of these materials may be added to the oral composition.

The present oral compositions can be readily prepared by simple mixing methods and from readily available components. However, it is important that the imidazoyl compound be first mixed with the nonionic active component before it is added to the oral vehicle, which typically contains water.

For example, a mouthwash or mouthwash can be prepared by first solubilizing the imidazole compound by emulsifying it in a nonionic surfactant before adding it to the water vehicle or the alcoholic water vehicle. Other ingredients, such as flavors, sweeteners, etc., may be added to the water vehicle either before or after the addition of the solubilized imidazole to the water vehicle.

The toothpaste can be prepared by first mixing the imidazole compound with the nonionic wetting agent in which it is solubilized, and then adding the thickening agent, such as carboxymethylcellulose, to form a gel, followed by the addition of polishes, water and other ingredients. The order in which the addition of the various ingredients takes place can be varied, provided that the imidazole compound is first solubilized in the nonionic wetting agent before it is added to the water component.

In the practical application of the invention, an oral composition according to the invention, such as a mouthwash or a toothpaste containing 1-imidazoyl-1- (p-chlorophenoxy) -3,3-dimethyl-2-butanone, is applied as an antigenic agent. agent, evenly on the tooth enamel in an amount which effectively improves oral hygiene, preferably about 1 to about 3 times daily at a Ph of about 5 to about 7.5.

The following particular examples further illustrate the present invention, but it is to be understood that the scope of the invention is not limited by these. All quantities and parts mentioned herein and in the appended claims are by weight unless otherwise indicated.

Example 1 Mouthwash Realistic Alcohol = 25% Climbazole = 0.3% Flavor (K-91-3863) = 0.22% Pluronic F 108 * = 3.0% Glycerol = 25% Sodium saccharin = 0.03% Water to 100% * Block polymer of about 80% by weight polyoxyethylene and about% by weight polyoxypropylene, the polyoxypropylene radical having a molecular weight of 3250, obtained from BASF Wyandotte Company Climbazole is mixed with Pluronic to a homogeneous and clear product before being added to the water-alcohol vehicle containing glycerol, flavoring and sodium saccharin.

The resulting product is effective in controlling gingivitis and treating periodontitis and is a simple means of improving oral hygiene when used regularly in the mouth 1 to 3 times a day.

The unexpectedly superior antigivine effect of this product is shown in Table 1, where the mouthwash of Example 1 was used as the experimental solution. This product also has antibacterial properties against Bacteroides assaccharolyticus and B. gingivalis.

Example 2 Toothpaste Ingredients wt% H 2 O 31.3 Na-benzoate 0.5 Na-saccharin 0.2 polyacylene glycol eol 25.0 Climbazole 1.0 carboxymethylcellulose 1.5 syioia-2442 3.0 zeo-493 35.0 sodium lauryl sulphate 1 .5 flavoring 1.0 grams 156.5 2.5 1.0 125, 0 7.5, 0 175 7.5, 0 1 H (OCH 2 CH 2) n NOH wherein n is an integer between 10 and 14, preferably 12.5 to 14 and having a molecular weight of 570 - 630 2 colloidal silicic acid 3 sodium aluminosilicate (silicic acid combined with 1% alumina) from Huber Co. 459 845 Climbazole is premixed with the polyethylene glycol before the carboxymethylcellulose is added to form a gel. To this gel are added with stirring Syloid, Zeo, sodium lauryl sulfate, flavoring, water, benzoate and saccharin. The benzoate and saccharin can be dissolved in the water before mixing with the other ingredients. Likewise, Zeo, flavoring and sodium lauryl sulfate can be premixed before being added to the crazy. This product also has good antimicrobial and anti-gingival properties.

Other conventional components may be substituted or added as previously described. For example, hydrated alumina or water-insoluble metaphosphate or dicalcium phosphate dihydrate and other polishing agents may be substituted for the alkali metal aluminum silicate (Zeo) or the colloidal silicic acid (Syloid), in whole or in part. Similarly, other nonionic surfactants instead of propylene substitutes oxide and ethylene oxide (Pluronic), such as the polyoxy hexane mono-higher fatty acid esters. -ethylene- It is understood that the above detailed description has been given for the purpose of illustration only and that changes may be made without departing from the scope of the invention. the above "summary" is provided for the convenience of technical researchers only and should not be construed as affecting the scope of the invention.

Claims (5)

459 845 21 P a t e n t k r a v Oral composition, preferably in the form of a mouthwash, having a pH of 5 - 5, for the treatment of gingivitis and periodonitis, characterized in that it comprises an oral vehicle and an effective amount of 0 1-5% by weight of the water-insoluble antiging agent, 1-imidazoyl-1- (p-chlorophenoxy) -3,3-dimethyl-2-butanone, solubilized in a nonionic compound containing a hydrophobic radical and 10 -A80 % by weight of hydrophilic units of polyoxyethylene of sufficient length to effect solubilization in the weight ratio of 3: 1 to 25: 1 of nonionic compound zantigingive agent, which agent is selectively active against the gram-negative anaerobic microorganisms Bacteriodes assaccharolyticus, Bacterioder blingival. An oral composition according to claim 1, characterized in that the nonionic compound contains a hydrophobic polyoxypropylene radical and hydrophilic polyoxyethylene radicals of sufficient length to effect subsequent solubilization in an aqueous vehicle, the weight ratio of hydrophilic: hydrophobic radicals in the nonionic compound is about 4: 1. An oral composition according to claim 1, characterized in that it comprises a water-alcohol vehicle, containing a nonionic surfactant as a nonionic solubilizer for said antigingbite agent selected from the group consisting of block polymers of propylene oxide and ethylene oxide, polyoxyethylene -hexitan-mono-higher-fatty acid esters comprising 10 - 80nol ethylene oxide per mole and mixtures thereof. 459 845 22 An oral composition according to any one of claims 1 to 3, in the form of a toothpaste having a pH of 5 to 7.5 for the treatment of gingivitis and periodonitis, characterized in that it comprises a dentally acceptable polishing agent, a liquid vehicle containing water and an effective amount of 0.1 to 5% by weight of the water-insoluble antiging agent, 1-imidazoyl-1- (p-crimphenoxy) -3,3-dimethyl-2-butanone, solubilized in 20 to 40% by weight of the composition of a nonionic wetting agent, which comprises at least one wetting agent selected from the group consisting of polyoxyethylene glycol and polyopropylene glycol in a weight ratio of 3: 1 to 25: 1 nonionic agent: antifungal agent, which agent is selectively active against the gram-negative the anaerobic microorganisms Bacteriodes assccharolyticus, Bacteriodes gingivalis and mixtures thereof. Oral composition according to claim 4, characterized in that glycerol, sorbitol or mannitol can be used instead of a part of the wetting agent, provided that the anti-gingival agent is solubilized.