MXPA06000699A - A doxycycline metal complex in a solid dosage form - Google Patents

Abstract

The present invention is a solid dosage form of a doxycycline metal complex. The present invention also includes a process for making a doxycycline metal complex in a solid dosage form. The process comprises the steps of (i) providing an aqueous solution of doxycycline or a physiologically acceptable salt thereof;(ii) admixinga metal salt with the aqueous solution;(iii) admixing a base to increase the pH of the aqueous solution, thereby forming a suspension of doxycycline metal;and (iv) drying the suspension, thereby forming a dry granulation of doxycycline metal complex.

Description

DOXICICLINE METAL COMPLEX IN A SOLID DOSAGE FORM FIELD OF THE INVENTION The present invention is directed to a doxycycline metal complex. More particularly, the present invention is directed to a solid dosage form of a doxycycline metal complex.

BACKGROUND OF THE INVENTION Doxycycline (6-deoxy-5-hydroxytetracycline monohydrate) is a broad-spectrum bacteriostatic compound that is effective against aerobic and anaerobic, gram-positive, gram-negative bacteria, as well as spirochetes, mycoplasmas, rickettsia, Chlamydia and some protozoa. It works by inhibiting protein synthesis in bacteria and protozoa, which effectively annihilates them. It is commonly used in the treatment of bacterial infections caused by these organisms, such as urinary tract infections, respiratory tract infections. superior, acne, gonorrhea, chlamydia, anthrax, lyme disease and others. Individuals taking doxycycline are notified that they should avoid iron supplements, ultivitamins, calcium supplements, antacids, or Ref. 169100 laxatives. These products can adversely reduce the effectiveness of doxycycline by reducing its absorption in the body. British Patent No. 1,360,998 to Villax discloses a process for the isolation of a-6-deoxytetracyclines from a crude reaction mixture. The patent also discloses that calcium salts of tetracyclines are suitable for oral preparations such as suspensions. However, it is known that calcium salts of doxycycline are particularly unstable in an alkaline pH environment. In addition, the process described by Villax, uses an organic solvent, that is, methanol. While organic solvents are frequently used to prepare pharmaceutically active ingredients, they are generally not desirable in the process of preparing a solid dosage form containing a pharmaceutically active ingredient. Clearly, the process described in Villax for the isolation of deoxytetracyclines could not result in a solid dosage form suitable for pharmaceutical administration to humans due to the residual solvent. Doxycycline is a very bitter-tasting drug. Currently, a metal salt of doxycycline is only available as a suspension of doxycycline and calcium. One advantage of the doxycycline and calcium complex suspension is that it has an acceptable taste. But many individuals find it an inconvenient liquid dosage form. Having no real alternative, i.e., a solid dosage form of a doxycycline metal complex, must tolerate the inconvenience. Another source of doxycycline is doxycycline hyclate. However, it can cause complications, such as esophageal ulceration. This may not be a problem with a solid dosage form of doxycycline. For example, a doxycycline and calcium complex chewable tablet, if available, may not cause ulceration of the esophagus because the drug may not be soluble and therefore could pass through the esophageal environment without damaging it. However, the production of a solid dosage form of a doxycycline metal complex is extremely difficult. For example, it is not known how to filter a metal complex of doxycycline in an aqueous suspension, such as doxycycline and calcium complex. The methods of the prior art have not made it possible to obtain reasonably pure doxycycline metal complex from an aqueous solution.

BRIEF DESCRIPTION OF THE INVENTION The present invention is directed to a solid dosage form of a doxycycline metal complex for pharmaceutical administration. The present invention includes a solid dosage form of a pharmaceutical composition comprising: (i) a doxycycline metal complex and (ii) one or more pharmaceutically acceptable excipients. The present invention also includes a process for producing a doxycycline metal complex in a solid dosage form. The process comprises the steps of (i) providing an aqueous solution of doxycycline or a physiologically acceptable salt thereof; (ii) mixing a metal salt with the aqueous solution; (iii) adding a base to increase the pH of the aqueous solution, thereby forming a doxycycline metal suspension; and (iv) drying the suspension, thereby forming a dry granulation of doxycycline metal complex. Optionally, the process may include the step of mixing one or more pharmaceutically acceptable excipients. The excipient may be added prior to the drying step of the suspension or after the doxycycline metal complex granulation is formed. In addition, the granulation can be further processed by filling the granulation into capsules or compressing it into tablets. In another embodiment, the process for producing a doxycycline metal complex in a solid dosage form comprises the steps of (i) providing an aqueous solution of doxycycline or a physiologically acceptable salt thereof; (ii) mixing a metal salt with the aqueous solution; (iii) adding a base to increase the pH of the aqueous solution, thereby forming a doxycycline metal complex suspension; (iv) mixing one or more pharmaceutically acceptable excipients with the suspension to absorb water, thereby forming a wet granulation; and (v) drying the wet granulation, thereby forming a wet granulation of doxycycline metal complex. Optionally, the step of 'mixing one or more pharmaceutically acceptable excipients can be carried out after the wet granulation is formed. In addition, the dry granulation can be further processed by filling the dry granulation into capsules or compressing it into tablets. In still another embodiment, the present invention is a method of treating bacterial infections, which comprises the step of administering a safe and effective amount of a doxycycline metal complex in a solid dosage form for an effective period of time, to a host in need of it. In addition, the invention includes a method for treating ailments resulting from microorganisms and / or bacteria, comprising the step of administering a safe and effective amount of a doxycycline metal complex in a solid dosage form for a period of time. effective, to a host in need of it.

DETAILED DESCRIPTION OF THE INVENTION For the purposes of the present invention, all percentages given denote percent by weight, unless otherwise specified. The doxycycline metal complex and the active ingredients of the present invention are used in a "safe and effective amount". This is understood to mean a sufficient amount of a compound or composition that will possibly modify the symptoms and / or condition to be treated, provided that the amount is low enough to avoid serious side effects. The amount of the compound, for example, doxycycline metal complex, which is considered safe and effective, will depend on several factors. For example, one should consider the condition and severity of the condition to be treated, the age, body weight, general health, sex, diet, and physical condition of the patient to be treated, the duration of treatment, the nature of concurrent therapy, the particular active ingredient to be employed, the particular pharmaceutically acceptable excipients used, the time of administration, method of administration, rate of excretion, drug combination, and any other relevant factors.

The term "pharmaceutically acceptable excipient" is understood to mean any pharmacologically inactive, physiologically inert material known to one skilled in the art, which is compatible with the physical and chemical characteristics of the particular doxycycline metal complex selected for use. The present invention is directed to a solid dosage form of a doxycycline metal complex for pharmaceutically acceptable administration to a human, ie any of the residual solvents or other impurities are at a level that is considered safe for human consumption. The doxycycline metal complex can be, for example, doxycycline and calcium complex, doxycycline and magnesium complex, doxycycline and sodium complex, or doxycycline and zinc complex. An advantage of the doxycycline metal complex is that it provides the user / patient, doxycycline and a mineral source which may be useful. For example, a doxycycline and calcium complex tablet could provide the user / patient with a source of doxycycline and a source of calcium. This is contrary to the teachings of the prior art, where it is taught that calcium inhibits the absorption of tetracycline. The inventors, however, have discovered that a therapeutic amount of doxycycline can be absorbed from a doxycycline metal solid, for example, doxycycline and calcium complex in solid dosage form, as taught by the present invention. Ideally, doxycycline has undergone complete complexation. This is understood to mean that at least about 75% by weight of the doxycycline is complex. More preferably at least about 90% has been complexed. It should be understood, however, that an excess of doxycycline or metal salt can be added to form the doxycycline metal complex. It has been hypothesized that the doxycycline metal complex has a mole ratio of metal to doxycycline of about 0.5 to about 3 in the solid dosage form. Preferably the ratio is from about 1.5 to about 2.5, and more preferably about 1: 2. The present invention also includes a pharmaceutical composition formulated in conjunction with pharmaceutically acceptable carriers or excipients and / or bioactive agents. The composition comprises (i) a doxycycline metal complex and (ii) one or more pharmaceutically acceptable excipients. Preferably, the pharmaceutical composition can take the form of a powder, capsule, tablet, coated tablet, aerosol, pellet, chewable tablet, lozenge, capsule filled with gelatin, and the like.

Suitable pharmaceutically acceptable excipients include, but are not limited to, polymers, resins, plasticizers, fillers, lubricants, binders, disintegrators, granulating agents, solvents, co-solvents, surfactants, preservatives, sweetening agents, flavoring agents, buffer systems, antioxidants, pharmaceutical grade dyes , pigments, and mixtures thereof. Polymers that can be used include, but are not limited to, hydroxypropyl ethylcellulose (HPMC) alone and / or in combination with hydroxypropylcellulose (HPC), carboxymethylcellulose, acrylic resins such as Eudragit®, methylcellulose, ethylcellulose, and polyvinylpyrrolidone or other preparations of Commercially available film coating. Suitable plasticizers include, but are not limited to, polyethylene glycol, propylene glycol, dibutyl phthalate, castor oil, acetylated monoglycerides, triacetin, and mixtures thereof. Examples of fillers include, but are not limited to, lactose, sucrose, maltodextrin, mannitol, starch, microcrystalline cellulose, and mixtures thereof. Lubricants that can be used include, but are not limited to, magnesium stearate, stearic acid, talc, and mixtures thereof.

Suitable binders include, but are not limited to, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, carbomer, povidone, acacia, guar gum, xanthan gum, tragacanth, calcium silicate, magnesium aluminum silicate, ethylcellulose, pregelatinized starch, and mixtures thereof. Particularly preferred are methylcellulose, carbomer, xanthan gum, guar gum, povidone and sodium carboxymethylcellulose. Disintegrants that may be used include, but are not limited to, crospovidone, sodium carboxymethyl starch, sodium starch glycolate, sodium carboxymethyl cellulose, alginic acid, clays, ion exchange resins, and mixtures thereof. Examples of surfactants include, but are not limited to, polyoxyethylene sorbitan grade acid esters, polyoxyethylene monoalkyl ethers, sucrose monoesters, lanolin ethers and esters, and mixtures thereof. Suitable preservatives include, but are not limited to, phenol, alkyl esters of parahydroxybenzoic acid, benzoic acid and salts thereof, boric acid and salts thereof, sorbic acid and salts thereof, chlorbutanol, benzyl alcohol, trimerosal, nitrate and phenylmercuric acetate, nitromersol, benzalkonium chloride, cetylpyridinium chloride, methyl paraben, propyl paraben, and mixtures thereof. Particularly preferred are the salts of benzoic acid, cetylpyridinium chloride, methyl paraben and propyl paraben. Antioxidants that may be used include, but are not limited to, tocopherols and derivatives thereof, ascorbic acid, beta-carotene, selenium, sodium bisulfite, sodium metabisulfite, ascorbyl palmitate, and mixtures thereof. Suitable sweeteners, include but are not limited to, sucrose, glucose, saccharin, aspartame, and mixtures thereof. Particularly preferred are sucrose and saccharin. Buffer systems that may be used include, but are not limited to, potassium, boric, carbonic, phosphoric, succinic, malic, tartaric, citric, acetic, benzoic, lactic, glyceric, gluconic, glutaric, glutamic, and mixtures. thereof. Particularly preferred are phosphoric, tartaric, citric and potassium acetate. Water is preferably used as the solvent. Although other solvents can be used. Suitable co-solvents include, but are not limited to, ethanol, glycerin, propylene glycol, polyethylene glycol, and mixtures thereof. The pharmaceutical compositions described herein are comprised of from about 0.1 weight percent (wt%) to about 99.9 wt%, preferably from about 5.0 wt% to about 50.0 wt%, and most preferably of about 10% by weight. weight to about 50% by weight of doxycycline metal complex, and from about 0.1% by weight to about 99.9% by weight, preferably from about 5.0% by weight to about 99.9% by weight, and most preferably of about 50% by weight Weight to about 90% by weight of one or more pharmaceutically acceptable excipients. The solid dosage form of a doxycycline metal complex is made using a new process. The process comprises the steps of (i) providing an aqueous solution of doxycycline or a physiologically acceptable salt thereof; (ii) adding a metal salt to the aqueous solution, (iii) adding a base to increase the pH of the aqueous solution, thereby forming a doxycycline metal complex suspension; and (iv) drying the suspension, thereby forming a dry granulation of doxycycline metal complex. . Optionally, one or more pharmaceutically acceptable excipients may be added before, during, or after each processing step. The doxycycline or physiologically acceptable salt may be, for example, doxycycline hyclate, doxycycline monohydrate, doxycycline carrageenan, doxycycline phosphate, or mixtures thereof. The doxycycline or physiologically acceptable salt is dissolved in an aqueous solution. Any suitable medium can be used to dissolve the doxycycline or doxycycline salt in the aqueous solution. Usually, all that is required is some form of mixing. The aqueous solution preferably is comprised of at least about 75% in weight of water. Other components may be included in the aqueous solution such as, for example, ethanol. The aqueous solution will generally have a pH that is in a range of about 1 to about 8. Suitable metal salts include, but are not limited to, calcium salts, sodium salts, magnesium salts, zinc salts, and mixtures of the same. A particularly preferred metal salt is calcium chloride. The metal salt is added with or without mixing, but it is usually mixed in solution. Approximately 1% by weight to about 50% by weight of the metal salt is added to the aqueous solution based on the total weight of the doxycycline formulation. Preferably, the metal salt is from about 1% by weight to about 25% by weight, more preferably 3% by weight to about 10% by weight. A base is added to the aqueous solution and mixed with the other components. The base is added in an effective amount to form a suspension of the doxycycline metal complex. Generally, the addition of the base raises the pH of the solution to a pH range of about 2.5 to about 8. Suitable bases include for example, sodium hydroxide, potassium hydroxide, triethanolamine, diethanolamine, monoethanolamine, sodium bicarbonate, and mixtures thereof. The amount of base that is added will depend on several factors, including the pH of the aqueous solution and the formation of the suspension. Generally, about 1% by weight to about 5% by weight of the base is added, based on the total weight of the doxycycline formulation. More preferably about 2% by weight to about 4% by weight of the base is added. The drying of the suspension can be carried out using a variety of techniques. For example, in one embodiment, a spray dryer is used and the suspension is sprayed onto an excipient. The suspension is filtered to remove the water. Other methinclude decanting, evaporation, freeze drying, tray drying, fluidized bed drying, and the like. In another embodiment, the process for producing a solid dosage form of a doxycycline metal complex comprises the steps of: (i) providing an aqueous solution of doxycycline or a physiologically acceptable salt thereof;; (ii) mixing a metal salt with the aqueous solution, (iii) adding a base to increase the pH of the solution, thereby forming a doxycycline metal complex suspension; (iv) mixing one or more pharmaceutically acceptable excipients with the suspension, thereby forming a wet granulation; and (v) drying the wet granulation, thereby forming a dry granulation of the doxycycline metal complex. Steps (i) - (iii) of this embodiment are the same as the previous described process that forms the solid dosage form of the suspension. This method, however, uses an excipient to aid in the formation of a wet granulation. The inventors have discovered that an excipient, for example, microcrystalline cellulose, will be absorbed and adsorbs the moisture in the suspension when it is mixed with the suspension. The result is a wet granulation or slurry having about 5% by weight to about 99% by weight of water. Preferably, the moisture in the wet granulation is about 25% by weight to about 60% by weight. By forming the wet granulation, the drying process can proceed more easily. One or more pharmaceutically acceptable excipients can be mixed in any process during any of the process steps. In addition, excipients can be added in more than one stage.

The wet granulation can be dried by pan drying, fluidized bed drying, decantation, evaporation, freeze drying, a combination thereof, or by other processes known to those skilled in the art. It is desirable that the doxycycline metal complex granulation be dried at a moisture content of about 1% by weight to about 15% by weight based on the total weight of the doxycycline metal complex granulation. moisture content should be less than about 10% by weight, most preferably at about 1% by weight to about 6% by weight The resulting doxycycline metal complex is in the form of a dry granulation consisting of granules and powder The dry granulation can be mixed with excipients such as lubricants, ie magnesium stearate.The final mixture can be further processed by filling it into capsules.The inventors have also discovered that the doxycycline metal complex granulation formed after the step drying is well suited for tableting, in fact, the formulator must choose, tabletting operations can be carried out if n the use of additional tableting excipients. Another significant advantage is, unlike other synthesis processes, the method of the present invention does not require a purification step to remove undesirable impurities. This makes the process more efficient and makes it possible for the tablets to be made directly from the doxycycline metal complex granulation. However, it should be understood that tabletting excipients can be incorporated. As previously noted, the excipients, i.e. lubricants, can be added before and / or after the drying step of the suspension or wet granulation. The excipients are simply added and mixed with the other components. In a preferred embodiment, the tablets are chewable tablets. This could be greatly beneficial for those who suffer from esophageal ulceration, since a chewable tablet of a doxycycline metal complex is not soluble in the esophageal environment. Therefore, the chewable table could pass through the esophagus in a harmless manner. In addition, the solid dosage form of the present invention may contain additional ingredients. For example, the additional ingredients may include natural and artificial flavors, sweeteners, colorants, coating excipients, binders, disintegrators, lubricants, and the like. The solid dosage form is generally administered orally in the form of tablets, capsules, powders, granules, lozenges, aerosols, pellets, chewable tablets, and the like. The excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinyl-pyrrolidone; fillers for example lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; tableting lubricant, for example magnesium stearate, talc, polyethylene glycol or silica; Disintegrators, for example potato starch, or acceptable wetting agents such as sodium lauryl sulfate, may be included to facilitate the formation of the tablet. In addition, the coatings can be applied onto the tablets using methods known in the art. The present invention also includes a method of treating bacterial infections. The method comprises the step of administering to a host, such as a human or animal, a safe and effective amount of a doxycycline metal complex, in solid dosage form. Examples of bacterial infections that can be treated with a doxycycline metal complex include urinary tract infections, upper respiratory tract infections, acne, gonorrhea, chlamydia, syphilis, anthrax, Lyme disease, and the like. The solid dosage form of a doxycycline metal complex can be used in the treatment of conditions caused by bacteria and microorganisms. Non-limiting examples of bacteria and microorganisms are gram-positive microorganisms, gram-negative microorganisms, aerobic bacteria, anaerobic bacteria, spirochetes, mycoplasmas, rickettsia, chlamydia, treponema, listeria, bacillus anthracis, fusiform fusobacterium, actinomyces israelii, clostridium, ureaplas to urealyticum, borrelia recurrentis, hemofilus ducreyi, yersinia pestis, francisella tularensis , vibrio cholerae, brucella, campylobacter fetus, bartonella bacillifor is, calymmatobacterium granulomatis, and protozoa. The treatment may require the administration of a safe and effective amount of a solid dosage form of a doxycycline metal complex for an effective period of time.

EXAMPLE 1 TABLE 1 A 20-25% solution of doxycycline hyclate was prepared by dissolving 16.5 g of doxycycline hyclate in water. A 50% solution of calcium chloride was also prepared by dissolving 5.6 g of calcium chloride in water. The doxycycline hyclate solution and the calcium chloride solution were combined and mixed according to the amounts specified in TABLE 1. Then, 5N sodium hydroxide was added to the mixture. This raised the pH of the mixture to about 5. Preferably the pH was raised to about 6, and most preferably, the pH was raised above about 6, but below about 8. This formed a doxycycline metal suspension of calcium . An excipient, microcrystalline cellulose (74.9 g), was then added to the suspension. The microcrystalline cellulose absorbed and adsorbed the moisture in the suspension, resulting in the formation of a wet granulation. The wet granulation was dried using a fluidized bed drier or tray to reduce the moisture content to less than 10%, and preferably from about 1% to about 6%, thereby forming a dry granulation. "through a 14 mesh screen .. 0.4 g of magnesium stearate was added as a lubricant, to form the final dry granulation. At this point, a colorant can be added. Dry granulation can now be used to fill gelatin capsules, or it can be compressed into tablets. Once the gelatin capsules or tablets are produced, a film coating can be applied over the tablets.

EXAMPLE 2 TABLE 2 The procedure of EXAMPLE 1 was followed with the exception that the weight percent of each ingredient was varied as indicated in TABLE 2 above. While the invention has been described above with reference to the specific embodiments thereof, it is evident that many changes, modifications, and variations can be made without departing from the inventive concept described herein. Accordingly, it is proposed to include all changes, modifications, and variations that fall within the spirit and broad scope of the appended claims. All patent applications, patents, and other publications cited herein are incorporated by reference in their entirety.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (23)

RETVINDICATIONS Having described the invention as above, the content of the following claims is claimed as property:

1. Solid dosage form of a doxycycline metal complex, characterized in that it is for pharmaceutical administration.

2. Solid dosage form according to claim 1, characterized in that the doxycycline metal complex is doxycycline and calcium complex.

3. Solid dosage form according to claim 1, characterized in that the solid dosage form is selected from the group consisting of powders, granules, tablets, coated tablets, - gelatin-filled capsules, pellets, and chewable tablets.

4. Solid dosage form of a pharmaceutical composition, characterized in that it comprises: (i) a metal complex of doxycycline in a solid form, and (ii) one or more pharmaceutically acceptable excipients.

Composition according to claim 4, characterized in that the doxycycline metal complex is doxycycline and calcium complex.

6. Composition according to claim 4, characterized in that the pharmaceutically acceptable excipient is selected from the group consisting of: polymers, resins, plasticizers, fillers, lubricants, binders, disintegrators, granulating agents, solvent, co-solvents, surfactants, preservatives, sweetening agents, flavoring agents, buffer systems, antioxidants, pharmaceutical grade dyes, pigments, and mixtures thereof.

7. Composition in accordance with the claim 4, characterized in that the pharmaceutically acceptable excipient is microcrystalline cellulose.

Process for producing a doxycycline metal complex in a solid dosage form, characterized in that it comprises the steps of: (i) providing an aqueous solution of doxycycline or a physiologically acceptable salt thereof; (ii) mixing a metal salt with the aqueous solution, (iii) adding a base to increase the pH of the aqueous solution, thereby forming a doxycycline metal complex suspension; and (iv) drying the suspension, thereby forming a dry granulation of doxycycline metal complex.

Process according to claim 8, characterized in that the doxycycline metal complex is doxycycline and calcium complex.

10. Solid dosage form according to claim 8, characterized in that the aqueous solution of doxycycline or a physiologically acceptable salt thereof is produced by dissolving doxycycline or a physiologically acceptable salt thereof in an aqueous solution resulting in a solution containing a pH range of about 1 to about 8.

Process according to claim 8, characterized in that the metal salt is selected from the group consisting of calcium salts, magnesium salts, sodium salts, zinc salts , and mixtures thereof.

Process according to claim 8, characterized in that the metal salt is calcium chloride.

13. Process according to claim 8, characterized in that the base is sodium hydroxide.

Process according to claim 8, characterized in that the granulation has a moisture level of less than about 10% by weight.

15. Process according to claim 8, characterized in that the drying step is carried out by a process selected from the group consisting of: spray drying, fluidized bed drying, tray drying, decantation, evaporation, freeze drying, and combinations thereof.

16. Process according to claim 8, characterized in that it additionally comprises the step of adding one or more pharmaceutically acceptable excipients, prior to the drying step.

Process according to claim 8, characterized in that it additionally comprises the step of adding one or more pharmaceutically acceptable excipients, after the formation of the granulation.

18. Process according to claim 8, characterized in that it additionally comprises the step of compressing the granulation, thereby forming tablets.

Process according to claim 8, characterized in that the doxycycline or a physiologically acceptable salt thereof is selected from the group consisting of: doxycycline hyclate, doxycycline monohydrate, doxycycline carragenate, doxycycline phosphate, and mixtures thereof. same.

20. Solid dosage form of a doxycycline metal complex, characterized in that it is produced by the process according to claim 8.

21. Process for producing a solid dosage form of a doxycycline metal complex, characterized in that it comprises the steps of: (i) providing an aqueous solution of doxycycline or a physiologically acceptable salt thereof; (ii) mixing a metal salt with the aqueous solution; (iii) adding a base to increase the pH of the solution, thereby forming a doxycycline metal complex suspension; (iv) mixing one or more pharmaceutically acceptable excipients with the suspension, thereby forming a wet granulation; and (v) drying the wet granulation.

22. Method of treatment of bacterial infections, characterized in that it comprises the step of: administering to a host in need thereof, a safe and effective amount of a doxycycline metal complex in a solid dosage form for an effective period of time.

23. Method of treatment of a condition resulting from microorganisms and / or bacteria, characterized in that it comprises the step of: administering to a host in need thereof, a safe and effective amount of a doxycycline metal complex in a dosage form solid for an effective period of time.