GB2414668A

GB2414668A - Sustained release delivery system for tetracycline compounds

Info

Publication number: GB2414668A
Application number: GB0419500A
Authority: GB
Inventors: Victor Pevzner; Marina Ruderman; Avi Avramoff
Original assignee: Dexcel Ltd Israel
Current assignee: Dexcel Ltd Israel
Priority date: 2004-06-03
Filing date: 2004-09-02
Publication date: 2005-12-07
Anticipated expiration: 2024-09-02
Also published as: GB0419500D0; GB2414668B

Abstract

An encapsulated two tablet dosage system comprising at least one quick release tablet and at least one delayed release tablet is disclosed, wherein each tablet has a diameter of greater than 3mm. A method of preparing such a two tablet delivery system is also provided. Also disclosed is a method for preparation of a pharmaceutical delivery system, by forming quick release cores with a diameter greater than 3mm, coating with an enteric coating to form a delayed release tablet and optionally coating to form quick release tablets. Also provided is an encapsulated pharmaceutical system comprising two tablets adapted to provide a therapeutically effective blood concentration level of minocycline.

Description

Title: TETRACYCLINE MODIFIED RELEASE DELIVERY SYSTEM Inventors: Victor

Pevzner, Marina Ruderman, and Avi Avramoff

FIELD OF THE INVENTION

The present invention relates to a delivery system for tetracyclines, and more particularly to a modified release system providing delayed release and controlled rapid release delivery.

BACKGROUND OF THE INVENTION

Minocycline, 7-dimethylamino-6-deoxy-6-demethyltetracycline, is a semisynthetic antibiotic, with a spectrum of activity similar to that of other tetracyclines, which primarily involves inhibition of bacterial protein synthesis by binding to the 30S subunit of the ribosome. Minocycline is effective against a wide variety of pathogenic microorganisms, such as -hemolytic streptococci, nonhemolytic streptococci, gram-negative bacilli, rickettsiae, spirochetes, Mycoplasma, and Chlamydia, including Haemophilus, Brucella, Listeria monocytogenes, Neisseria gonorrhoeae, campylobacter, Vibrio cholerae, Yersinia pestis, Bacteroides, Enterobacter, E. colt, Klebsiella, Shigella. Strep viridans group, Strep pneumoniae, Strep. pyogenes, Chlamydia, Clostriduim, and Treponema pallidum.

Minocycline has been found to be more effective than other tetracyclines against tetracycline resistant staphylococci.

Minocycline and methods for its preparation are described in US 3,148,212 and US 3,226,436.

Uses of tetracyclines include treatment and prevention of acne, respiratory tract infections such as bronchitis, pneumonia and sinusitis, and infections of skin, genital, and urinary systems.

Minocycline hydrochloride is available in conventional capsule and tablet dosage forms, as well as in a modified release dosage form comprising quick release and delayed release pellets.

EP0310814B1 to American Cyanamid teaches use of spherical granules comprising tetracycline compounds, including minocycline, for controlled release in the intestine. The granules are in the shape of spheres, having a diameter in the range of from 0.1 to 2.5 mm.

Each granule has a very thin coating of polymer, which resists erosion in the stomach but erodes rapidly in the intestine. By preventing release in the stomach, nausea and dizziness following oral administration are avoided. The granules are filled into the capsules or compressed into tablets.

s EP0418565BI to American Cyanamid describes a delivery system for minocycline, comprising quick release granules which release minocycline in a medium having pH less than 3.9, and pH sensitive polymer coated spherical granules, releasing minocycline in a medium having pH from 4.0 to 7.5. Both the quick release granules and the enteric coated granules are taught as having diameters in the range of from 0.1 to 2.5 mm.

0 EP0558913BI to American Cyanamid describes pulsatile, once-a-day delivery systems for minocycline, providing a therapeutically effective blood concentration for a sustained period of time of up to about twenty four hours. The delivery system comprises quick release granules, adapted to release minocycline in a medium with pH less than 3.9; coated spherical slow release granules comprising excipients with minocycline; and a uniform pH sensitive coating which is a blend of two polymers, where at least one polymer is non-pH sensitive and the other is pH sensitive. The quick release granules provide a first pulse of minocycline in the stomach. The coated granules release a small amount of minocycline in the stomach, with the major part released in the intestine. Again, both types of granules have diameters in the range of from 0.1 to 2.5 mm.

SUMMARY OF THE INVENTION

The background art does not teach or suggest a two-tablet encapsulated modified release delivery system for tetracyclines, comprising a quick release tablet and a delayed rapid release tablet, wherein both types of tablet have diameters greater than 3 mm.

2s The present invention overcomes this deficiency of the prior art by providing a two tablet dosage system comprising: a. at least one quick release tablet, comprising an effective antibacterial amount of a tetracycline compound or a non-toxic acid addition salt or a pharmaceutically acceptable salt thereof; an effective amount of at least one pharmaceutically acceptable excipient; and optionally a substantially uniform polymer coating on said tablet; and b. at least one delayed release tablet, comprising an effective antibacterial amount of a tetracycline compound or a non-toxic acid addition salt or a pharmaceutically acceptable salt thereof; an effective amount of at least one pharmaceutically acceptable excipient; and a substantially uniform pH sensitive coating on said tablet, characterized in that said quick release tablet and said delayed release tablet each have a diameter greater than about 3 mm.

It should be noted that the terms "tetracycline compound" or "a tetracycline" refer to any molecule of the tetracycline class, as described in greater detail below.

Optionally and preferably, the tablet diameters are in the range of from about 3 mm to about 5.5 mm. More preferably, the diameters are in the range of from about 4.5 to about 5.5mm. Most preferably, the quick release tablet has a diameter in the range of form about 5.0 to about 5.2 mm, and the delayed release tablet has a diameter in the range of from about 5.1 to about 5.4 mm. Optionally, the tablet diameter may be about as large as the capsule 0 diameter, which is optionally from about 4 to about 10 man; preferably, as noted above, the tablet diameter is somewhat smaller than the capsule diameter. Also optionally, the tablet diameter is at least about 3 mm.

Optionally and preferably, the tetracycline compound is minocycline. Alternatively or additionally, the tetracycline compound may comprise at least one of chlortetracycline (US Patent No. 2482055), demeclocycline (US Patent No. 2878289), doxicycline (US Patent No. 3019260), lymecycline (US Patent No. 3042716), meclocycline (US Patent No. 2984686), methacycline (US Patent No. 2984686), oxy-tetracycline (US Patent No. 2516080), rolitetracycline (ZA Patent No. 316975), tetracycline (US Patent No. 2699054) and pharmaceutically acceptable salts thereof.

The present invention also provides a method for the preparation of a pharmaceutical delivery system, comprising granulating an effective antibacterial amount of a tetracycline or a non-toxic acid addition salt or a pharmaceutically acceptable salt thereof and an effective amount of at least one pharmaceutical acceptable excipient in the presence of a granulating solution; drying and milling the granulate and compressing said granulate to form quick release tablets of diameter greater than about 3 mm; coating at least a portion of said quick release tablets with a substantially uniform coating comprising a pH sensitive polymer to form delayed release tablets.

Optionally and preferably, the granulate is prepared by wet granulation, drying and milling. Alternatively, the granulate may be prepared by a dry mix method.

Optionally and preferably, the method further comprises the step of at least partially filing a hard or soft shell capsule with a major proportion of quick release tablets and a minor proportion of delayed release tablets. More preferably, the proportion of quick release tablets is from about 43 to about 73 parts by weight, and the proportion of delayed release tablets is from about 27 to about 57 parts by weight.

Optionally and preferably, the method further comprises the step of sealing the capsule.

Optionally and preferably, the pH sensitive polymer is credible in a medium having a pH in the range of from about 4.0 to about 7.5.

Among the many advantages of the present invention are that it provides two types of compressed tablets in a capsule formulation, thereby providing bioequivalence to the prior art products but optionally with a smoother distribution of blood levels over an extended period of time compared to the immediate release products. The manufacturing process is more precise and easier to control.

lo Although it should be noted that the tablet coating may optionally be a film or polymer coating, other types of coatings may optionally be substituted, such as a sugar

coating for example.

According to preferred embodiments of the present invention, there is provided a pharmaceutical multiple tablet system adapted to provide a therapeutically effective blood concentration level of a tetracycline compound or a pharmaceutically acceptable addition salt or a pharmaceutically acceptable salt thereof, comprising: at least one quick release tablet, comprising an effective antibacterial amount of tetracycline compound or a non-toxic acid addition salt or a pharmaceutically acceptable salt thereof, an effective amount of at least one pharmaceutically acceptable excipient; and at least one delayed release tablet, comprising an effective antibacterial amount of tetracycline compound or a non-toxic addition salt or a pharmaceutically acceptable salt thereof; an effective amount of at least one pharmaceutically acceptable excipient; and a substantially uniform pH sensitive coating, characterized in that at least one of said quick release tablet and said delayed release tablet has a diameter of greater than 3 mm.

as Preferably, said tetracycline compound comprises minocycline or a pharmaceutically acceptable addition salt or a pharmaceutically acceptable salt thereof. Also preferably, said addition salt is selected from the group consisting of hydrochloric, sulfonic, and trichloroacetic acid salts. More preferably, said addition salt is a hydrochloric acid addition salt.

Preferably, said system is adapted to provide said therapeutically effective blood concentration level for a sustained period of time. More preferably said sustained period of time is up to 24 hours.

Preferably, said quick release tablet and said delayed release tablet each has a diameter in the range of from about 3 mm to about 5.5 mm. More preferably, said quick release tablet and said delayed release tablet each has a diameter in the range of from about 4.5 mm to about 5.5 mm. Most preferably, said quick release tablet has a diameter in the range of from about 5 rnm to about 5.2 mm, and said delayed release tablet has a diameter in the range of from about 5.1 to about 5.4 mm. Optionally and most preferably, said quick release tablet has a thickness in the range of from about 5 mm to about 5.6 mm.

Also optionally and most preferably, said delayed release tablet has a thickness in the range of from about 3.9 mm to about 4.5 mm.

Preferably, the system further comprises a gelatin capsule, wherein said quick release 0 tablets and said delayed release tablets are contained within said capsule.

Optionally and preferably, the system features a major proportion of quick release tablets, and a minor proportion of delayed release tablets. More preferably, said major proportion comprises from about 43 to about 73 parts by weight of quick release tablets, and wherein said minor proportion comprises from about 27 to about 57 parts by weight of delayed release tablets.

Preferably, said quick release tablet further comprises a substantially uniform film forming coating. More preferably, said film-forming polymer coating is selected from the group comprising sugar, methyl cellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate. Most preferably, said film-forming polymer coating comprises Opadry. Also most preferably, said Opadry coating comprises from about 2 weight percentage to less than about weight percentage of film content based on total weight of said tablet. Also most preferably, said Opadry coating comprises from about 1 to about 5 weight percentage of film content based on the weight of said tablet.

Preferably, said Opadry coating comprises from about 2 to about 3 weight percentage of the weight of said tablet.

Also preferably, said effective antibacterial amount of minocycline or non-toxic acid addition salt or a pharmaceutically acceptable salt thereof comprises from about 25 mg to about 400 ma. More preferably, said effective antibacterial amount of minocycline comprises from about 80 mg to about 280 ma. Most preferably, said effective antibacterial amount of minocycline comprises from about 20 mg to about 200 ma.

Preferably, said quick release tablets comprise from about 10 to about 70 parts by weight of minocycline and from about 90 to about 30 parts by weight of excipient based upon parts by weight of minocycline and excipient combined. More preferably, said quick release tablets comprise about 50 to about 60 parts by weight of minocycline and from about about 40 to about 50 parts by weight of excipient based upon 100 parts by weight of minocycline and excipient combined.

s Preferably, said delayed release tablets comprise from about 10 to about 80 parts by weight of minocycline and from about 90 to about 20 parts by weight of excipient based upon parts by weight of minocycline and excipient combined.

Also preferably, said pharmaceutical excipient comprises at least one of the group comprising binders, diluents, glidants, colorants, disintegrating agents, and lubricants.

lo Also preferably, said pharmaceutical excipient is selected from the group comprising microcrystalline cellulose, polyvinylpyrrolidone, hydroxypropylmethyl cellulose, lactose, sodium carboxymethylcellulose. More preferably, said lubricant is selected from the group comprising stearate salts, stearic acid, talc, castor oil, hydrogenated palm oil, some type of starch, polyethylene glycol, sodium stearyl fumarate, glycerol behenate, waxes, or a combination thereof. Most preferably, said stearate salt is magnesium stearate. Also most preferably, said magnesium stearate is present in an amount of about 1 %.

Preferably, said glidant is selected from the group comprising anhydrous colloidal silica, tribasic calcium phosphate, calcium silicate, powdered cellulose, magnesium silicate, magnesium triplicate, silicon dioxide, starch, talc, or a combination thereof. More preferably, glidant is anhydrous colloidal silica. Most preferably, said anhydrous colloidal silica is present in an amount of 0.33 %.

Preferably, said binder is be selected from the group comprising starch, low molecule weight hydroxypropyl cellulose (HPC), low molecular weight hydroxypropyl methyl cellulose (HPMC), low molecular weight carboxy methyl cellulose, ethylcellulose, gelatin polyethylene oxide, acacia, dextrin, magnesium aluminium silicate, polymethacrylates, or a combination thereof. More preferably, said binder is povidone. Most preferably, said povidone is present in an amount of about 5 %.

Preferably, said disintegrant is selected from the group comprising croscarmellose sodium, crospovidone, sodium carboxymethyl starch, pregelatinized starch, microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminium silicate, or a combination thereof. More preferably, said disintegrant is croscarmellose sodium. Most preferably, said croscarmellose sodium is present in an amount of about 3 %.

Preferably, said diluent is microcrystalline cellulose. More preferably, said microcrystalline cellulose is present in an amount of about 30 %. Also more preferably, said diluent is selected from the group comprising starch, lactitol, lactose, sucrose, an inorganic calcium salt, or a combination thereof.

Preferably, said colorant is selected from the group comprising ferric oxide yellow and red iron oxide, or a combination thereof.

Preferably, said substantially uniform pH sensitive coating of said delayed release tablet is selected from the group comprising carbomers, cellulose acetate phtalate, polymethacrylates, polyvinyl acetate phthalate, zein, hypromellose phtalate, or a combination thereof. More preferably, said substantially uniform pH sensitive coating of said delayed release tablet comprises hypromellose phtalate. More preferably, said hypromellose phtalate lo is present in an amount of from about 10 to about 20 weight percent with regard to said core.

Preferably, said uniform pH sensitive coating further comprises a plasticizer. More preferably, said plasticizer is selected from the group comprising dibutyl sebacate, polyethylene glycol and propylene glycol, dibutyl phthalate, tributyl citrate, triethyl citrate, acetylated monoglyceride, acetyl tributyl citrate, triacetin, dimethyl phthalate, benzyl i5 benzoate, butyl and/or glycol esters or fatty acids, refined mineral oils, oleic acid, castor oil, corn oil, camphor, glycerol and sorbitol, or a combination thereof. Most preferably, said plasticizer is triethyl citrate. Also most preferably, said triethyl citrate is present in an amount of about 2.3 weight percentage of the weight of the coating.

Preferably, said substantially uniform pH sensitive coating further comprises an anti adhesion/anti-caking agent. More preferably, said antiadhesion/anti-caking agent is selected from the group consisting of talc, tribasic calcium phosphate, calcium silicate, silica colloidal anhydrous, magnesium silicate/trisilicate, or a combination thereof. Most preferably, said anti-adhesion/anti-caking agent is talc. Also most preferably, said talc is present in an amount of 2.3 weight percent of said coating.

Preferably, said gelatin capsule is selected from the group comprising a hard shell gelatin capsule and a soft shell gelatin capsule.

Also preferably, said substantially uniform pH sensitive coating further comprising a wetting agent. More preferably, said wetting agent is selected from the group comprising sodium lauryl sulphate, benzalkonium chloride, benzethronium chloride, docusate sodium, poloxamer, polyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, sorbitan esters or combinations thereof. Most preferably, said wetting agent is sodium lauryl sulfate. Also most preferably, said sodium lauryl sulfate is present in an amount of about 2.3 weight percent of said coating.

Preferably, release of about 50 percent to about 70 percent of said minocycline from said quick release tablet occurs in less than about 90 minutes in a medium having a pH of less than about 3.9. More preferably, said release occurs in about 60 minutes. Most preferably, said release occurs at a pH in the range of from about 1 to about 2.5.

Preferably, said release occurs in the human stomach. Also preferably, release of about 50 percent to about 70 percent of said tetracycline compound from said delayed release tablet occurs in less than about 90 minutes in a medium having a pH of from about 4 to about 7.5. More preferably, said release occurs in the human upper intestinal tract. Most preferably, said release occurs in the duodenum/jejunum.

lo According to other preferred embodiments of the present invention, there is provided a method for the preparation of the pharmaceutical multiple tablet system as described above, comprising an effective antibacterial amount of a tetracycline compound or a non-toxic acid addition salt or a pharmaceutically acceptable salt thereof and an effective amount of at least one pharmaceutical acceptable excipient using dry mix technology.

Preferably, said tetracycline compound is minocycline or a pharmaceutically

acceptable salt.

According to other preferred embodiments of the present invention, there is provided a method for the preparation of the multiple tablet system as described above, comprising an effective antibacterial amount of a tetracycline compound or a non-toxic acid addition salt or a pharmaceutically acceptable salt thereof and an effective amount of at least one pharmaceutical acceptable excipient not using extrusion.

Preferably, said tetracycline compound is minocycline or a pharmaceutically

acceptable salt.

According to other preferred embodiments of the present invention, there is provided a 2s method for the preparation of a pharmaceutical delivery system, comprising granulating an effective antibacterial amount of a tetracycline compound or a non-toxic acid addition salt or a pharmaceutically acceptable salt thereof and an effective amount of at least one pharmaceutical acceptable excipient in the presence of a granulating solution; drying; milling; optionally mixing with disintegrant, lubricant, glidant compressing said granulate to form quick release cores having diameter greater than about 3 mm; coating at least a portion of said quick release cores with a substantially uniform enteric coating to form delayed release tablets; optionally coating cores by readily erodible coating to form quick release

tablets.

Preferably, said enteric coating comprises a polymer which is pHsensitive and credible in a medium having a pH in the range of from about 4 to about 7.5.

Preferably, the method further features at least partially filling a hard or a soft shell capsule with a pharmaceutical delivery system with a major proportion of said quick release tablets and a minor proportion of said delayed release tablets and optionally sealing said capsules.

Preferably, said tetracycline compound is minocycline or a pharmaceutically

acceptable salt.

According to other preferred embodiments of the present invention, there is provided a lo method for treating a bacterial disease, comprising administering to a subject in need thereof, the pharmaceutical multiple tablet system as described above. Preferably, said bacterial disease is caused by bacteria selected from the group comprising as a-hemolytic streptococci, nonhemolytic streptococci, gram-negative bacilli, rickettsiae, spirochetes, Mycoplasma, and Chlamydia, including Haemophilus, Brucella, Listeria monocytogenes, Neisseria gonorrhoeae, campylobacter, Vibrio cholerae, Yersinia pestis, Bacteroides, Enterobacter, E. co li, Klebsi en a, Shigella. Strep viridans group, Strep pneumonias, Strep. pyogenes, Chlamydia, Clostriduim, and Treponema pallidum.

More preferably, said bacterial disease is selected from the group comprising acne, respiratory tract infections, infections of skin, genital, and urinary systems.

According to other preferred embodiments of the present invention, there is provided a pharmaceutical multiple tablet system adapted to provide a therapeutically effective blood concentration level of a tetracycline compound or a pharmaceutically acceptable addition salt or a pharmaceutically acceptable salt thereof, comprising: at least one quick release tablet, comprising said tetracycline compound, an effective amount of at least one pharmaceutically as acceptable excipient; and optionally a substantially uniform readily credible coating; at least one delayed release tablet, comprising tetracycline compound or a pharmaceutically acceptable salt thereof, an effective amount of at least one pharmaceutically acceptable excipient; and a substantially uniform pH sensitive coating.

Preferably, said system is adapted to provide such a concentration level for a sustained period of time of up to about twenty-four hours.

More preferably, said tetracycline compound comprises minocycline or an acceptable salt thereof.

Optionally and preferably, the system may be characterized in that at least one of said quick release tablet and said delayed release tablet has a diameter of greater than 3 mm.

According to other preferred embodiments of the present invention, there is provided an encapsulated pharmaceutical system comprising two tablets, adapted to provide a therapeutically effective blood concentration level of minocycline.

According to other preferred embodiments of the present invention, there is provided s an encapsulated pharmaceutical system comprising two tablets, wherein said system is bioequivalent to the conventional MR formulation of minocycline. Preferably, the system comprises: at least one quick release tablet, comprising an effective antibacterial amount of tetracycline compound or a non-toxic acid addition salt or a pharmaceutically acceptable salt thereof, an effective amount of at least one pharmaceutically acceptable excipient; and lo optionally a substantially uniform polymer coating; and at least one delayed release tablet, comprising an effective antibacterial amount of tetracycline compound or a non-toxic addition salt or a pharmaceutically acceptable salt thereof; an effective amount of at least one pharmaceutically acceptable excipient; and a substantially uniform pH sensitive coating, characterized in that at least one of said quick release tablet and said delayed release tablet has a diameter of greater than 3 mm.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is herein described, by way of example only, with reference to the accompanying drawing, wherein: FIG. I shows in vitro dissolution of Table I formulation according to the present invention; and FIG. 2 shows mean in vivo plasma concentration-time curves for the formulation of the present invention as compared to a reference preparation. 2s

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention provides a once-daily modified release formulation of a a tetracycline compound or a pharmaceutically acceptable acid addition salt, e.g. hydrochloric, sulfonic, trichloroacetic acid salts, and the like, preferably the hydrochloric acid addition salts. Optionally and preferably, the tetracycline compound comprises minocycline. A preferred embodiment of the present invention provides a capsule comprising at least two types of tablet, wherein a first tablet type provides quick release, and a second tablet type provides delayed release. The first tablet type is optionally enteric coated, preferably film coated, and the second tablet type is also optionally enteric coated. It should be noted that although the present invention is mainly described with regard to minocycline as the preferred embodiment, this is for the purposes of discussion only and is not meant to be limiting in any way, as optionally any tetracycline may be used, as previously described.

The quick and substantially complete release of the active ingredient from the quick s release component is such that about 50-70 percent of the total amount of the minocycline in the formulation, is released in less than about 90 minutes, and preferably less than about 60 minutes, in a medium having a pH of less than about 3.9, and, preferably in a range of from about 1.0 to about 2.5, such as in the human stomach. Any optional polymer coating of the quick release component is therefore specifically rapidly and substantially erodible or 0 dissolvable to permit these conditions to be met; preferably, the enteric coating is a pH sensitive polymer. This provides a first pulse of release of the active ingredient, such as minocycline, preferably in the stomach. This quick initial release allows therapeutic plasma drug levels to be rapidly attained, such drug levels being at least that amount determined by in vivo clinical evaluation or in vitro microbiological assay to treat successfully infections caused by the invading organism or organisms.

The substantially complete release of delayed release component is such that about 30-50 percent of the total amount of the active ingredient is released in less than about 90 minutes in a medium having a pH in the range of from about 4.0 to about 7.5, as in the human upper intestinal tract and particularly in the duodenum/jejunem. Therefore, the pH sensitive polymer coating must be specifically rapidly and substantially completely credible or dissolvable to permit these conditions to be met.

Optionally and preferably, the pharmaceutical delivery system of the present invention contains from about 25 mg to about 400 mg of minocycline or non-toxic acid addition salt thereof and most preferably from about 80 mg to about 280 ma. Preferably, the 2s quick release component, the delayed release component, or both independently contain from about 20 to about 200 mg of minocycline.

Preferably, the system comprises a major proportion of coated or uncoatedquick release tablets, and a minor proportion of delayed release tablets. More preferably, the proportion of quick release tablets is from about 43 to about 73 parts by weight, and the proportion of delayed release tablets is from about 27 to about 57 parts by weight, based on parts by weight of quick release and delayed release tablets combined.

Most preferably, the ratio is from about 58:42 by weight of quick release tablets delayed release tablets, based on 100 parts by weight of quick release and delayed release tablets combined. The use of a higher ratio of quick release tablets in proportion to delayed release tablets is believed to result in a higher absorption of minocycline because minocycline is preferentially absorbed in the duodenum and jejunurn, although without wishing to be limited by a single hypothesis. Cores

The core of each of the quick release tablet and the delayed release tablet has a diameter which is greater than about 3 mm. Optionally and preferably, the tablet diameters are in the range of from about 3.0 mm to about 5.5 mm. More preferably, the diameters are in the range of from about 4.5 to about 5.5 mm. Most preferably, the quick release tablet has a 0 diameter in the range of from about 5.0 to about 5.2 mm, with thickness preferably in the range of from about 5.0 to about 5.6 mm. The entericcoated tablet most preferably has a diameter in the range of from about 5. 1 to about 5.4 mm, with thickness preferably in the range of from about 3. 9 to about 4.5 mm.

The cores of the quick release and enteric-coated tablets comprise a tetracycline or pharmaceutically acceptable salts thereof, together with excipients. More preferably, the tetracycline is minocycline, most preferably minocycline hydrochloride.

Any conventional excipients used in the pharmaceutical and chemical field that are compatible with the active ingredient may optionally be used, such as binders, diluents, colorants, disintegrating agents, lubricants, glidants etc. Illustrative non-limting excipients suitable for use herein include but are not limited to, microcrystalline cellulose, povidone, croscarmellose sodium, magnesium stearate, red iron (ferric) oxide, yellow iron (fernc) oxide, silica colloidal anhydrous, and optionally mixtures of any of the foregoing. The excipients are preferably the same for both cores, optionally with the exception of colorants such as red or yellow iron oxide for example.

The amounts of minocycline and excipients which comprise the core of quick release and delayed-release tablets can vary broadly but will usually be in the range of from about 10 to about 80 parts by weight of minocycline and from about 20 to about 90 parts by weight of excipient based upon 100 parts by weight of minocycline and excipient combined. Preferably, the core comprises from about 55 to about 60 parts by weight of minocycline and from about 40 to about 45 parts by weight of excipient based upon 100 parts by weight of minocycline and excipient combined.

The lubricant is optionally and preferably magnesium stearate, which most preferably is present in an amount of about 1%. Alternatively or additionally, the lubricant may optionally be selected from the group consisting of stearate salts (calcium, zinc, glycerin etc), stearic acid, talc, castor oil, hydrogenated palm oil, hydrogenated vegetable oil, hydrogenated castor oil, light mineral oil some type of starch, polyethylene glycol, sodium stearyl fumarate, compritol (glyceryl behenate), glyceryl palmitostearate, magnesium lauryl sulfate, medium chain triglycerides, poloxamer, sodium benzoate, sodium chloride, sodium lauryl sulfate, waxes such as carnauba wax, or a combination thereof.

Optionally and more preferably, the core further comprises a glidant. Preferably, the glidant is anhydrous colloidal silica, which most preferably is present in an amount of about 0.33%. Alternatively or additionally, the glidants may be selected from the group comprising tribasic calcium phosphate, calcium silicate, powdered cellulose, magnesium silicate, 0 magnesium trisilicate, silicon dioxide, starch, talc, or a combination thereof.

According to other preferred embodiments of the present invention, the core may further comprise a binder. More preferably, the binder is povidone, which most preferably is present in an amount of about 5%. Alternatively or additionally, the binder may be selected from the group comprising starch, hydroxypropyl cellulose, h,vpromellose, low molecular weight carboxy methyl cellulose, carboxy methyl cellulose sodium, ethylcellulose, gelatin, polyethylene oxide, acacia, dextrin, magnesium aluminium silicate, polymethacrylates, alginic acid, carrageenan, cellulose acetate phthalate, ceratonia, chitosan, sucrose, cottonseed oil, dextrates, dextrose, glucose, glyceryl behenate, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, maltodextrine, maltose, m ethyl cellulo se, mi crocrysall ine cellulose, poloxamer, polydextrose, sodium alginate, steari c acid, sunflower oil, zein, or a combination thereof.

The disintegrant is optionally and preferably croscarmellose sodium, which is most preferably present in an amount of about 3%. Alternatively or additionally, the disintegrant may be selected from the group comprising crospovidone, sodium carboxymethyl starch (sodium starch glycolate), starch, pregelatinized starch, calcium carboxymethyl cellulose, magnesium aluminium silicate, alginic acid, tribasic calcium phosphate, carboxymethylcellulose sodium, cellulose, chitosan, silica colloidal anhydrous, docusate sodium, guar gum, hydroxypropyl cellulose, methylcellulose, microcrystalline cellulose, povidone, sodium alginate or a combination thereof.

The diluent is optionally and preferably microcrystalline cellulose, which most preferably is present in an amount of about 30%. Suitable forms of microcrystalline cellulose are, for example, the materials sold as Avicel-PH-101 and Avicel-PH-105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA., U.S.A.).

Alternatively or additionally, the diluent or filler may be selected from the group comprising starch, lactitol, lactose, sucrose, a suitable inorganic calcium salt, cellulose, cellulose silicified, cellulose acetate, compressible sugar, confectioner's sugar, dextrates, dextrin, dextrose, ethylcellulose, fructose, fumaric acid, glyceryl palmitostearate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, polydextrose, polymethacrylates, simethicone, sodium alginate, sodium chloride, sorbitol, starch pregelatinized, sugar pellets, tragacanth, trehalose, xylitol or a combination thereof.

Optionally and preferably the core further comprises a colorant, more preferably selected from the group consisting of ferric oxide yellow and red iron oxide, or a combination thereof. Optionally, any conventional/known colorants may be applied. Examples include 0 but are not limited to, Curcumin, Riboflavin, Tartrazine, Quinoline yellow, Sunset yellow FCF, Carmine, Carmosine, Amaranth, Panceau 4R, Erithrosine, Allura red AC, Patent blue V, Indigo carmine, Brilliant blue FCF, Chlorophylls, Copper Complexes of chlorophylls and chlorophyllins, Green S. Caramel, brilliant black BN, vegetable carbon, Caratenoids, Xanthaphylls, Beetroof red, Anthocyanins, Callcium carbonate, Titanium dioxide, Iron hydroxides, Aluminum, or a combination thereof.

Coatings The quick release tablet is uncoated, or optionally coated with a film forming polymer. The film-forming polymer, if used, can vary widely in type, and amount, which correlates to film thickness. It is important, however, that any film forming polymer is either somewhat erodible in gastric juice and/or is used in an ultra-thin layer or layers to permit release of an entire amount of tetracycline compound in the stomach, the importance of which has been set forth above. Examples of film forming polymers which are suitable for this purpose include sugar, methyl cellulose, ethylcellulose, hydroxyethylcellulose, 2s hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate or a combination thereof. Some of these coatings are pH sensitive as described below, but they are thin layer coatings, which are destroyed in the stomach. Such a thin layer of an enteric coating would not be expected to cause any undesirable delay in the release. The thin layer of enteric coating is used to obtain better resistance of the tablet and to improve convenience of handling during the encapsulation process, and so forth.

Although from about 1 weight percent to less than about 10 weight percent of film content based on the total weight of the film coated tablets is suitable for most readily gastric juice erodible polymers, it is preferred to use from about 1 weight percent to about 5 weight percent of any film in order to permit the release of the entire amount of tetracycline compound in the stomach.

In a preferred embodiment of the present invention, the film coating comprises Opadry, which most preferably is present in an amount of from about 1 to about 5% of the s core.

The pH sensitive coating for the delayed rapid release tablet is optionally and preferably hypromellose, because this polymer degrades at relatively lower pH values in comparison with other pH sensitive polymers such as methacrylic polymers for example. The ratio of coating to core is optionally and preferably in a range of from about 11% to about 0 18%. Alternatively or additionally other coatings may optionally be selected from the group comprising carbomers, cellulose acetate phtalate, hydroxypropyl methylcellulose acetate succinate, polymethacrylates, polyvinyl acetate phthalate, zein, carnauba wax, guar gum, shellac or a combination thereof. Upon reaching the duodenum/jejunem, the pH-sensitive polymer dissolves, and quick, complete release of minocycline occurs.

Is The enteric coating may optionally further comprise a plasticizer, which is preferably triethyl citrate, which is most preferably present in an amount 9. 1% of coating. Alternatively and additionally, the plasticizer may optionally be selected from the group comprising dibutyl sebacate, polyethylene glycol,propylene glycol, dibutyl phthalate, tributyl citrate, acetylated monoglyceride, acetyl tributyl citrate, diacetin, triacetin, dimethyl phthalate, diethyl phthalate, benzyl benzoate, butyl and/or glycol esters or fatty acids, refined mineral oils, oleic acid, castor oil, corn oil, camphor, acetyl monoglyceride, cellulose acetate phthalate, chlorbutanol, dextrin, diethyl phthalate, glycerin monostearate, hypromellose phthalate, mannitol, palmitic acid, polymethacrylate, polyvinyl acetate phthalate, stearic acid, triethanolamine, lanolin alcohols, glycerol and sorbitol, or a combination thereof.

2s The enteric coating may optionally further comprise a wetting agent, optionally and more preferably for enhancing degradation of the coating, which is preferably sodium lauryl sulfate, which is most preferably present in an amount of 1-3-% of the coating. Alternatively and additionally the wetting agent may optionally be selected from the group comprising: benzalkoniurn chloride, benzethronium chloride, docusate sodium, hypromellose, poloxamer, polyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, sorbitan esters, or a combination thereof.

The enteric coating may optionally further comprise an anti-adhesion/anticaking agent to prevent adhesion of the tablets during the coating process. This agent is preferably talc, which is most preferably present in an amount of from about l to about 3% of the coating. Alternatively and additionally the anti-adhesion/anti-caking agent may optionally be selected from the group comprising: tribasic calcium phosphate, calcium silicate, silica colloidal anhydrous, magnesium silicate/trisilicate, or a combination thereof.

s Process According to a preferred embodiment, the cores of both the slow release and the delayed rapid release tablets are prepared by granulation. The process comprises preparation of a solution of Povidone in water, and granulation of a mixture of minocycline hydrochloride, microcrystalline cellulose, croscarmellose sodium and colorants. The 0 granulate is dried in conventional equipment and milled. Preferably it is dried in a conventional fluidizing system to a low moisture level, e.g. , about 3 to about 7 percent.

Alternatively, other techniques can be used, such as dry mix for example.

Optionally and preferably croscarmellose sodium, anhydrous colloidal silica and magnesium stearate are then added.

Two types of tablets are compressed from the final mixture.

The hard shell capsules used in the present invention are generally comprised of gelatin, water and optionally, FD&C colorants, opacifying agents such as titanium oxide, sulfur dioxide to prevent any decomposition or a combination of any of the foregoing. They generally comprise two sections, one slipping over the other, completely surrounding the no filling.

The soft shell capsules used in the present invention are generally a soft, globular, gelatin shell somewhat thicker than the shell of the hard shell capsule. The gelatin is usually plasticized by the addition of glycerin, sorbitol, or a similar polyol. They may also contain a preservative to prevent the growth of fungi, and/or one or more of such optional ingredients as colorants, water and opacifying agents, for example.

Examples

The following are illustrative examples of formulations according to the present invention, for the purposes of illustration only and without any intention of being limiting.

Part I relates to the formulations; Part II relates to in vitro data with one formulation according to the present invention; and Part III relates to the in vivo data with the same formulation according to the present invention.

Part I: Formulations The following formulations listed below are exemplary formulations according to the present invention, any of which may optionally be produced according to the above described production method. These formulations are intended as examples only of formulations according to the present invention, without any intention of being limiting. The following examples illustrate formulations with different core ingredients (diluents, binders, disintegrants, lubricants, absence and presence of colorants) and coating ingredients (pH sensitive and usual coating agents, plasticizers, absence and presence of wetting and lo anticaking agents).lO8 mg of Minocycline Hydrochloride are equal to 100 mg of Minocycline as base.

Table 1: Composition of Minocycline 100 mg MR Capsules (containing 108. 00 mg of hydrochloride saltform of the active ingredient)

_

Name of Constituent Function of! Quantity per Capsule (mg) Constituent Cores: I 0 Minocycline Hydrochloride therapeutic 108.00 mg L. agent _,, ___,,,,,, ,, ,,,,_, Microcrystalline cellulose I diluent 53.4 mg Povidone binder _ 9.0 mg Crosc rmello e_dum _ dis_tegrant _ __ 5.4mg_ esium stearate I lubricant 1.8 ma Red iron (ferric) oxide colorant Yellow iron (ferric) oxide colorant 0.3 mg __ Silica colloidal anhydrous - _ **Purified water solvent N.D Total cores 180 me = DELAY QUICK ^ m; RELEi$E: . RELEASE:

At 'each tablet

core^,com'prises: cord compri es 40% of the. 60 of the labeled Amount, labeled amount . ;. substances' a., r Target cod, , . 72 maid. 108- me: _._.... ... . . Hypromellose phthalate pH sensitive 10 mg _coa ing Triethyl citrate plasticizer 1.0 my Opadry OY-S-24932 Pink coating 3.0 mg **Purified water solvent N.D N.D **Ethanol solvent N.D --- TIC ^ -', ' '\ ;:'''^^,I'2;.;";' -. ..... . .. ... . ... ,, ....

Carnauba wax polishing traces traces agent I _ C a edght:I ___, __ 83mg _ ___1,,11mg_ Hard Gelatin Capsule I i 76 mg- Total target weight of capsule: I | 270 ma_ 01 08mg Minocycline Hydrochloride equivalent to 100mg of Minocycline ha e.

s **Evaporates during the process Table 2: Composition of Minocycline 100 mg MR Capsules (containing 108. 00 mg of hydrochloride salt form of the actz've ingrediert) _.

Name of Constituent | Function of I Quantity per Capsule (mg) | Constituent Cores: I ine Hydrochloride therapeutc 108.00 mg _ _ agent. _ _ _ Microcrystalline cellulose diluent] 53.4 mg Povidone _ binder._ 9.0mg,,, ,, Crospovidone disinterant 7.2 mg _ _ Mm_ arate __ lubricant ___ 1.8 mg Silica colloidal anhrous glidant 0. 6 mg **fur fied water __, N.D _ __; Total cores 180 mE _. .... .. _ Y Tablet tvDes: ' , DELAYED.. I, QUICK W;....r ",\!s \ M =..' .' .; ,:., ' : . cor.'e cop ^ > - mpses , ;< - 40%-. ;: --of 73t A, . . e=A 2 -; . slibstance) substancej

. .. -- Taret core weicht: . . 72 ma 108 me _,- . ,, .... .. . ., .. . .. ,,, . ,, .. _ Hypromellose phthalate pH sensitive 10 mg..DTD: -

Triethyl citrateplasticizer 1.0 mg Opadr,y OY-S-24932 Pinkcoating 3.0 mg **Purified watersolvent N.D N.D **Ethanolsolvent __N.D _ I Polishln: Carnauba waxpolishing traces I traces :t: __ _ 83mg_ | 111m$ _psule:- --! __,,, 76 mg I I Total target weight of capsule: L _ 270 mg l 01 08mg Minocycline Hydrochloride equivalent to 1 00mg of Minocycline ba' ,e.

**Evaporates during the process Table 3: Composition of Minocycline 100 mg MR Capsules (containing 108. 00 mg of hydrochloride saltform of the active ingredient) l Name of Constituent Function of Quantity per Capsule (mg) ! Constituent I Cores. _ I- I_ 0 Minocycline Hydrochloride therapeutic 1 108.00 mg Microcrystalline cellulose diluentl 57.2 mg Povidone binder 7.0 mg Croscar_ellose sodium _ disinteant _ _ 5.4 mg Magnesium stearate lubricant 1.8 ma __ Slicacolloida anhydrous __ glidant ___ 0.6 mg **Purified water solvent N.D Total cores 180 me - - .--_ DELAYED. QUICK RELEASE: RELEASE: (Each tablet, , (Each tablet . ,,, ,, car, e com'6is; , core.'comp,rises 40% the'^ I' 60% of the ;, ,.- labetedam'ount ainount > I'. . r i, f d-, / . 2 A ' ' ' substance)' 22. , substance)

_

9:. ; .72ig.- . .108 my Hypromellose phthalate pH sensitive 10 mg _ coating Triethyl citrate plasticizer 1.0 mg Opadry Y- 1-7000 White coating 3.0 mg **Purified water solvent N.D N.D **Ethanol solvent N.D

---

Polishing. . ..

Carnauba wax polishing tracestraces _ Coated tab e target w i_t. in 83m _ _I Img Hard Gel_tin Capsule: L i 76 mg Total target weight of capsule: 270 mg s 01 08mg Minocycline Hydrochloride equivalent to 1 00mg of Minocycline ha e.

**Evaporates during the process Table 4: Composition of Minocycline 100 mg MR Capsules (containing 108. 00 mg of s hydrochloride saltform of the active ingredient) Name of Constituent! Function of | Quantity per Capsule (mg) Constituent I Cores: _

... __ _ _ _.. . .... .__...DTD: 0 Minocycline Hydrochloride therapeutic 108.00 mg __age crocrystalline cellulose l _ _ diluent] 7.2 mg__ _ Povidone bindery 7.0 mg Croscarmello e sodium _ disintegrant,,, 5 4 mg Magnesium stearate lubricant 1.8 mg __ Silica colloidal anhydrous _ elidant __ 0.6 mg **Purified water solvent N.D Total cores 180 ma Tablet ties: ... ; <. DELAYED ' :; QUICK;; , . RELEASE: RELEASE: - core con;'es 40%the. , .60 .of - labeiedrant Ibid amount . ' . , ., I. . '. . ' ' .; ' . Ii; . 'A. ' i!, . ' , , . | , 1, F; ' < . i JSt < =) ,,

-

Taret core weiht: . .> , ,., .. 72 mai;,,, -> , 108 ma Hypromellose phthalate pH sensitive 6.34 mg _. _, ..,, _,,, ,_ __coating Triethyl citrate Plasticizer _ 0 64 ma Opadry Y-1-7000 White coating 3.0 mg **Purified water solvent N.D N.D * *Ethanol solvent N.D Polishin: : -; :. . :ii;:;. s.... r In;. ;;;;7;'; L., ... _._ an...... ..

Carnauba wax polishing traces traces Coated tablet target weight 1 79_g,, I Illm Hard Gelatin Capsule: 76 ma_ Total target weight of capsule: 266 mg 0108mg Minocycline Hydrochloride equivalent to 100mg of Minocycline ha e.

**Evaporates during the process Table 5: Composition of Minocycline 100 mg MR Capsules (containing 108. 00 mg of hydrochloride saltform of the active ingredient) Name of Constituent Function of | Quantity per Capsule (mg) Constituent I _. _........

<amp-, i,, it__ _ in_ 0 Minocycline Hydrochloride therapeutic 108.00 mg Microcrystalline cellulose diluent 57.2 me Povidone binder 7.0_g_ Croscarmellose sodium disintegrant 5.4 mg _

-

Magnesium stearatelubricant 1.8 rng Silica colloidal anhydrous Lglidant 0. 6 mg **Purified waterlsolvent N.D Total cores 180 ma

-

Tablet t,ypes: DELAYED QUICK RELEASE. i ', RELEASE: (Each tablet (Each.tablet core comprises core comprises 40Yo of the. 60% of the labeled amount labeled amount I. . - . of d.ri'g Drug . . . P,, ,,,, , , at; a, , a, s ( Tarp) - .. ... A,; .... _. _, _ Target core weight: . . .... ; .;. If. . ... i;; . 72 misty... .i lO8m' ' _ _: : ... .. _. ! I,, . . ,$ A, .,, d, ..... !' Jl Hydroxypropyl Methylcellulose pH sensitive 8.36 mg Acetate Succi ate coating _ _ __ _ Sodium lauryl sulfate wetting agent 0.25 mg Talc l anticaking 2.39 mg _ _ _ _ _1 ___gent Opadry Y-1-7000 White coating 3.0 mg **Purified water solvent _ N.D L N.D **Ethanol solvent N.D Carnauba wax | polishing traces traces Coated tablet target weight:, i 83mg 1 111mg Har_ Gelatin Capsule. I 76 mg _ _. _ __ __ _ _._ _.... _ _._ _... ...

Total target weight of capsule: ! I 270 mg 01 08mg Minocycline Hydrochloride equivalent to 1 00mg of Minocycline ha; e.

**Evaporates during the process s Table 6: Composition of Minocycline 100 mg MR Capsules (containing 108.00 mg of hydrochloride saltform of the active ingredient) l Name of Constituent | Function of Quantity per Capsule (mg) ! Consfftuent i __..... _. __..... _ _- _, :.' ' ' ' 1..

0 Minocycline Hydrochloride therapeutic 108.00 mg __ agent Microcrystalline cellulosediluen 57.2 ma_ Povidonebinder _ 7.0 mg Croscarmellose sodiumdisinteerant 5 4 ma Magnesium stearatelubricant _ 1.8 mg _ Silica colloidal anhydrousclidant 0.6 mg **Purified watersolvent N. D Total cores 180 me Tablet tom: DELAY A A QUICK RELEASE: - RELEASE (Each; tablet. ' ,. (each'' tables. . 6.,' , Scorers, i - ship es I,, ^. 4,09fo' of. they'd'' ; ,60% th^e "" " ^'f",''-' .' ' 'la Child; - Id amount At. ""'.,4'^: ,'!',' i;''gi it'' Off-,! g, ^ .: . .substanc;;^; . substances _.. . ... - i Score weight: . ,., . . . . 72im ' ,' 108 ma _, . . .. . . ...... . Hydroxypropyl Methylcellulose pH sensitive 5.32 mg Acetate Succinate coating Sodium lauryl sulfate wetting agent 0.16 ma_ Talc anticaking 1.52 mg agent I Opadry Y- 1-7000 White Icoating 3.0 mg **Purified waterysolvent N.D N.D _ __ **Ethanolsolvent N.D Polishin: _ ___ _ Carnauba wax polishing traces traces Coated tablet target weight: 1 79 mg _ I Illmg Hard Gela in Capsule I I 76 mg Total target weight oicapsule. I 266 ma 01 08mg Minocycline Hydrochloride equivalent to 1 00mg of Minocycline ha e.

**Evaporates during the process Table 7: Composition of Minocycline 100 mg MR Capsules (containing 108.00 mg of hydrochloride saltform of the active ingredient) Name of Constituent! Function of Quantity per Capsule (mg) IConstitn nt Cores: 0 Minocycline Hydrochloride I therapeutic 108.00 mg _ aged 00 Ludipress Diluent and 87.0 mg binder I Sodium Stearyl Fumaratelubricant 4.0 ma Silica colloidal anhydrousfan 1.0 mg Total cores 200 me Tablet tamp:: DELAYED i QUICK RELEASE: RELEASE: (Edchtablett. (ach.tablet . i, , ' . A; t;\ .t, . . , , , A. . . . . core' c;omprises core comprises ! , A 40% Bathe. 6Q of the ;u.^ .^ . . iabeledt. .labelamount^ it' , . ' 4 1! Eli,, ! , ,,, , stir; ^ i... . .- of drug...; Big oydr7'g substance)_ Target core wed t: 80 ma 120 ma Hypromellosephthalate pH sensitive 10.91 mg Trethyl citrate] plasticizer 1.09 mug Opadry Y- 1-7000 White | coating 4.0 mg I__ agent _ | __ **Purified water solvent N. D I N.D **Ethanol solvent N. D Posses: .. if. . .... ,,:.,, ,^.i..

- . ...... _ Carnauba wax polishing traces traces l - _ _. ._ L. . agen.t _ __ 1. .. ._.q Coated tablet target weight: I 92 mg 12 Hard Gelatin Cansule. ' 76 me Total target weight of capsule. L ' 292 mg 0108mg Minocycline Hydrochloride equivalent to 100mg of Minocycline ba;e.

00 Ludipress (BASF's product)consists of 93 2% lactose monohydrate and 3. 5 0.5 % each of povidone (Kollidone 30) and crospovidone (Kollidone CL) **Evaporates during the process s Table 8: Composition of Minocycline 100 mg MR Capsules (containing 108.00 mg of hydrochloride salt form of the active ingredient) Name of Constituent I Function of Quantity per Capsule (mg) Constituent Cores: 0 Minocycline Hydrochloride therapeutic 108.00 mg 00 Ludipress: Diluent andl 87.0 mg ibinder I Sodium Stearyl Fumarate lubricant 4.0 mg Silica colloidal anhydrous _ glidant 1.0 mg _ _.... _ __ _ _. .. _ Total cores 200 ma Tablet tvues: . . . a: via, . i At,. At.

. : . . ; care can. Are mprses ^ ; , . % offs; 60% Of the labeled amount labeled amount oidrug. of drug . f. . subsce};^ ^ substance)

... ._ ma_;. ....... - Taret core weight: .80 me. i, 120 me ___..... . r. , .. - Hypromellose phthalate pH sensitive 7.27 mg i coating Triethyl citrate! Plasticize 0.73 mg Opadry Y- 1-7000 White I coating 4.0 mg _ _agent. ._...DTD: **Purified water solvent N.D N.D * *Ethanol solvent N.D Polishing. . . ; Carnauba wax polishing traces traces Coated tablet target weight: 88 mg _ _124 mu Hard Gelatin CaDsule: 76 mg Total target weight of capsule: 288 mg _ _ _ __ _. __ __.__ ___.__ _.___ _.__ _ O 1 08mg Minocycline Hydrochloride equivalent to 1 00mg of Minocycline base.

0 00 Ludipress (BASF's product) consists of 93 it 2% lactose monohydrate and 3.5 0.5 % each of povidone (Kollidone 30) and crospovidone (Kollidone CL) **Evaporates during the process s Table 9: Composition of Minocycline 100 mg MR Capsules (containing 108.00 mg of o hydrochloride salt form of the active ingredient) Name of Constituent | Function of I Quantity per Capsule (mg) | Constituent Cores: .: . - :.

0 Minocycline Hydrochloride therapeutic 108.00 mg agent 00 Ludipress Diluert and 89.0 mg binder Magnesium stearate lubricant 2.0 mg _Silica colloidal anhydrous _ glida it 1.0 mg Total cores 200 me Tablet types. . DELAYED: . QUICK RELEASE: - RELEASE: >,,,, ,< , ,,, ,, i,; by, Lath,- ' qS,joh, tab,le,t, . corpse eom,p,'',iSeS-A, ,c, to, re, c, ompr,ises, labeled At last' I' . '. ' ;:of-. .'' . 'A In__ substaneeJ;. i' substance: Target core weight:80 my I20 ma Eudragit L-30 pH sensitive5.20 mg coating _ __ _. _ TriethYI citrate plasticizer 0.52 me - Talc antiadhesion 1.56 mg Opadry Y-1-7000 Whitecoating 4.0 mg agent **Purified watersolvent N.D N.D **Ethanolsolvent I N.D Carnauba waxpolishing traces traces __ght. 87.3 ma: 124 mg _ Hard Gelatin Capsule: 76 my Totaltarg tweightf capsule: . . . . 287.3,mg,,, __ 01 08mg Minocycline Hydrochloride equiv; lent to l 00mg of Minocycline base.

00 Ludipress (BASF's product) consists of 93 2% lactose monohydrate and 3. 5 0.5 % each of povidone (Kollidone 30) and crospovidone (Kollidone CL) **Evaporates during the process PART II - In vitro Dissolution Study An in vitro dissolution study was performed with the formulation shown in Table 1 above. The results are shown in Figure 1. The method for determining dissolution was performed as follows.

lo Each of six minocycline tablets according to the present invention was inserted into individual dissolution cell each of which contained 900 ml HCI (0.1 N). After one hour, the dissolution medium was changed to 900 ml buffer USP pH 6.8 for two hours. The sample was stirred with a VanKel basket stirrer (Van Kel Inc., USA) at 900 RPM. Samples were automatically drawn from each dissolution cell to test tubes every 15 minutes as shown.

is Samples were analyzed by a W (ultraviolet) light detection device. The amount of drug released was calculated according to a standard set of calculations that are known in the art.

PART III - Bioavailabilitv Study This Example describes a bioequivalence study of two Minocycline 100 mg MR formulations after multiple dose administration in healthy male volunteers.

A bioequivalence study was performed in order to assess the relative bioavailability of the test product Minocycline 100 mg MR capsules of Dexcel Ltd. (the formulation shown in Table 1 was used) in comparison tothe reference product Minocin MR 100 mg capsules of Cyanamid of Great Britain after multiple dose administration. The study was designed as monocentric, open, randomized, multiple dose, two-period crossover study in healthy volunteers with a wash-out period of 16 days between the last dose in period 1 and the first dose in period 2, such that each volunteer served as his own control. Twenty six healthy, male volunteers were planned for and concluded the study.

At each period, a total of 6 capsules of either formulation were administered once daily to fasting volunteers on 6 consecutive days. Blood samples were withdrawn before each daily administration and at the following times: O.S, 1, 1.5, 2, 2.5, 3, 3.5, 4, ,4.5, 5, 6, 8, 10, 12, 14 and 24 hours after the last dose on day 6 in each period.

Plasma concentrations of Minocycline were determined using HPLC analytical method with UV detection.

s For each volunteer-period and for each analyte, the main pharmacokinetic parameter, AUC, was computed from the plasma concentration-time curve using the trapezoidal method from zero to 24 hours after the sixth administration.

The minimum (Css-min) and maximum (Css-max) steady state plasma concentrations, and the time to maximum concentration (Tmax) were observed directly from the curves.

0 The peak to trough fluctuation (PTF) expressed as a percentage was computed as [(Css-max - Css-min)/Css-average], and the swing expressed as a percentage was computed as [(Css-max - Css-min)/Css-min].

TABLE 10: PHARMACOMNETIC PARAMETERS: AUCss Css-max Css-min (ng x hour/ml) (ng/ml) (ng/ml) MINOCYCLINE 100mg MR 10417.90 2217.34 786. 76 174.76 175.02 52.44 (DEXCEL) (6725.84; 14756.86) (545.05; 1190.91) (103 59; 305. _._

MINOCIN MR 100mg 10051.22 2154.30 751.48 157.26 175.80 60.55 (CYANAMID) (6166.63; 14447.81) (440.33; 1059.44) (99 65; 314.52) _. ._ (Coefficient of Variation) 15% 19% 20% RATIO* 1.04 1.05 1.01 (90% ANOVA C.I.) (0.96; 1.11) (0.96; 1.14) (0.92; 1.11) Tmax Peak to Trough Swing (hours) Fluctuation (PTF) (%) MINOCYCLINE 100mgMR 2.83+ 1.22 142.3226. 37 373.53+ 118.71 DEXCEL) (100; 5.00) (94.46; 196.46) (182.07; 619.21) \4INOCIN MR 100mg 2.63 1.06 139.21 24.92 358.83 t 132.25 CYANAMID) (1.00; 4.50) (98.29; 182.63) (192.24; 671.82)

IFFERENCE

STIMATE** 0.25 2.34 19.88 range) (-3.00; 3.00) (-29.89; 59.72) (-228.08; 176.93) (90% non parametric C.I.) (-0.25; 0.75) (-5.25; 11.08) (-13 34; 46.29) o The presented values for all pharmacokinetic parameters are mean + SD and (range).

* The presented ratios are the geometric means of the ratios between test and the reference parameters. Parametric estimators and Parametric Confidence Intervals, based on the linear model with logarithmic transformation (multiplicative model), are brought.

s ** The presented difference is the median difference with its corresponding range. 90% non-parametric Confidence Intervals for the median difference with its corresponding median estimate was computed by the method of Hauschke et al., which does not require the restrictive assumption of equal period effect as previous methods.

Figure 2 shows the mean plasma minocycline levels for a formulation of the present lo invention in accordance with Example 1, shown in Table 1, as compared to the reference product.

As can be seen, the formulation according to the present invention provides equivalent bioavailability to that of the reference product. This is a surprising result to one of ordinary skill in the art, and a result which the art would teach away from expecting, since the prior art (known) product uses the complicated technology of spheroids, while the present invention uses a more simple production technology involving tablets. The formulation of the present invention is constructed such that it is possible to use tablets in place of spheroids, which would not be expected by one of ordinary skill in the art.

It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub comb inati on.

Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims. Citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention.

Claims

1. A pharmaceutical multiple tablet system adapted to provide a therapeutically effective blood concentration level of a tetracycline compound or a pharmaceutically acceptable acid addition salt or a pharmaceutically acceptable salt thereof, comprising: at least one quick release tablet, comprising an effective antibacterial amount of said tetracycline compound or a non-toxic acid addition salt thereof or a pharmaceutically acceptable salt, an effective amount of at least one pharmaceutically acceptable excipient; and at least one delayed release tablet, comprising an effective antibacterial amount of said tetracycline compound or a non-toxic addition salt thereof or a pharmaceutically acceptable salt; an effective amount of at least one pharmaceutically acceptable excipient; and a substantially uniform pH sensitive coating, characterized in that at least one of said quick release tablet and said delayed release tablet has a diameter of greater than 3 mm.

2. The system of claim I, wherein said tetracycline compound comprises minocycline or a pharmaceutically acceptable acid addition salt or a pharmaceutically acceptable salt thereof.

3. The system of claim I, wherein said addition salt is selected from the group consisting of hydrochloric, sulfonic, and trichloroacetic acid salts.

4. The system of claim 3, wherein said addition salt is a hydrochloric acid addition salt.

5. The system of claim 1, wherein said system is adapted to provide said therapeutically effective blood concentration level for a sustained period of time.

6. The system of claim 5, wherein said sustained period of time is up to 24 hours.

7. The system of claim 1, wherein said quick release tablet and said delayed release tablet each has a diameter in the range of from about 3 mm to about 5.5 mm.

8. The system of claim 7, wherein said quick release tablet and said delayed release tablet each has a diameter in the range of from about 4.5 mm to about 5.5 mm.

9. The system of claim 8, wherein said quick release tablet has a diameter in the range of from about 5 mm to about 5.2 mm, and said delayed release tablet has a diameter in the range of from about 5.1 to about 5.4 mm.

10. The system of claim 9, wherein said quick release tablet has a thickness in the range of from about 5 mm to about 5.6 mm.

11. The system of claim 9, wherein said delayed release tablet has a thickness in the range of from about 3.9 mm to about 4.5 mm.

12. The system of claim 1, further comprising a gelatin capsule, wherein said quick release tablets and said delayed release tablets are contained within said capsule.

13. The system of claim 1, comprising a major proportion of quick release tablets, and a minor proportion of delayed release tablets.

14. The system of claim 13, wherein said major proportion comprises from about 43 to about 73 parts by weight of quick release tablets, and wherein said minor proportion comprises from about 27 to about 57 parts by weight of delayed release tablets.

15. The system of claim 1, wherein said quick release tablet further comprises a substantially uniform film-forming coating;

16. The system of claim 15, wherein said film-forming polymer coating is selected from the group comprising sugar, methyl cellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate.

17. The system of claim 15 wherein said film-forming polymer coating comprises Opadry.

18. The system of claim 17, wherein said Opadry coating comprises from about 2 weight percentage to less than about 10 weight percentage of film content based on total weight of said tablet.

19. The system of claim 18, wherein said Opadry coating comprises from about 1 to about 5 weight percentage of film content based on the weight of said tablet.

20. The system of claim 19, wherein said Opadry coating comprises from about 2 to about 3 weight percentage of the weight of said tablet.

21. The system of claim 2 wherein said effective antibacterial amount of minocycline or non-toxic acid addition salt or a pharmaceutically acceptable salt thereof comprises from about 25 mg to about 400 ma.

22. The system of claim 21, wherein said effective antibacterial amount of minocycline comprises from about 80 mg to about 280 ma.

23. The system of claim 22, wherein said effective antibacterial amount of minocycline comprises from about 20 mg to about 200 ma.

24. The system of claim 2, wherein said quick release tablets comprise from about to about 70 parts by weight of minocycline and from about 90 to about 30 parts by weight of excipient based upon 100 parts by weight of minocycline and excipient combined.

25. The system of claim 24, wherein said quick release tablets comprise about 50 to about 60 parts by weight of minocycline and from about about 40 to about 50 parts by weight of excipient based upon 100 parts by weight of minocycline and excipient combined.

26. The system of claim 2, wherein said delayed release tablets comprise from about 10 to about 80 parts by weight of minocycline and from about 90 to about 20 parts by weight of excipient based upon 100 parts by weight of minocycline and excipient combined.

27. The system of claim 1, wherein said pharmaceutical excipient comprises at least one of the group comprising binders, diluents, glidants, colorants, disintegrating agents, and lubricants.

28. The system of claim 1, wherein said pharmaceutical excipient is selected from the group comprising microcrystalline cellulose, polyvinylpyrrolidone, hydroxypropylmethyl cellulose, lactose, sodium carboxymethylcellulose.

29. The system of claim 27 wherein said lubricant is selected from the group comprising stearate salts, stearic acid, talc, castor oil, hydrogenated palm oil, some type of starch, polyethylene glycol, sodium stearyl fumarate, glycerol behenate, waxes, or a combination thereof.

30. The system of claim 29, wherein said stearate salt is magnesium stearate.

31. The system of claim 30, wherein said magnesium stearate is present in an amount of about 1 %.

32. The system of claim 27, wherein said glidant is selected from the group comprising anhydrous colloidal silica, tribasic calcium phosphate, calcium silicate, powdered cellulose, magnesium silicate, magnesium trisilicate, silicon dioxide, starch, talc, or a combination thereof.

33. The system of claim 32, wherein said glidant is anhydrous colloidal silica.

34. The system of claim 33, wherein said anhydrous colloidal silica is present in an amount of 0.33 %.

35. The system of claim 27, wherein said binder is be selected from the group comprising starch, low molecule weight hydroxypropyl cellulose (HPC) , low molecular weight hydroxypropyl methyl cellulose (HPMC), low molecular weight carboxy methyl cellulose, ethylcellulose, gelatin polyethylene oxide, acacia, dextrin, magnesium aluminium silicate, polyinethacrylates, or a combination thereof.

36. The system of claim 35, wherein said binder is povidone.

37. The system of claim 36, wherein said povidone is present in an amount of about 5 %.

38. The system of claim 27, wherein said disintegrant is selected from the group comprising croscarmellose sodium, crospovidone, sodium carboxymethyl starch, pregelatinized starch, microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminium silicate, or a combination thereof.

39. The system of claim 38, wherein said disintegrant is croscarmellose sodium.

40. The system of claim 39, wherein said croscarmellose sodium is present in an amount of about 3 %.

41. The system of claim 27, wherein said diluent is microcrystalline cellulose.

42. The system of claim 41, wherein said microcrystalline cellulose is present in an amount of about 30 %.

43. The system of claim 27, wherein said diluent is selected from the group comprising starch, lactitol, lactose, sucrose, an inorganic calcium salt, or a combination thereof.

44. The system of claim 27, wherein said colorant is selected from the group comprising ferric oxide yellow and red iron oxide, or a combination thereof.

45. The system of claim 1, wherein said substantially uniform pH sensitive coating of said delayed release tablet is selected from the group comprising carbomers, cellulose acetate phtalate, polymethacrylates, polyvinyl acetate phthalate, Rein, hypromellose phtalate, or a combination thereof.

46. The system of claim 45, wherein said substantially uniform pH sensitive coating of said delayed release tablet comprises hypromellose phtalate.

47. The system of claim 46, wherein said hypromellose phtalate is present in an amount of from about 10 to about 20 weight percent with regard to said core.

48. The system of claim 1, wherein said uniform pH sensitive coating further comprise a plasticizer.

49. The system of claim 48, wherein said plasticizer is selected from the group comprising dibutyl sebacate, polyethylene glycol and propylene glycol, dibutyl phthalate, tributyl citrate, triethyl citrate, acetylated monoglyceride, acetyl tributyl citrate, triacetin, dimethyl phthalate, benzyl benzoate, butyl and/or glycol esters or fatty acids, refined mineral oils, oleic acid, castor oil, corn oil, camphor, glycerol and sorbitol, or a combination thereof.

50. The system of claim 49, wherein said plasticizer is triethyl citrate.

51. The system of claim 50, wherein said triethyl citrate is present in an amount of about 2.3 weight percentage of the weight of the coating.

52. The system of claim 1, wherein said substantially uniform pH sensitive coating further comprises an anti-adhesion/anti-caking agent.

53. The system of claim 52, wherein said anti-adhesion/anti-caking agent is selected from the group consisting of talc, tribasic calcium phosphate, calcium silicate, silica colloidal anhydrous, magnesium silicate/trisilicate, or a combination thereof.

54. The system of claim 53, wherein said anti-adhesion/anti-caking agent is talc.

55. The system of claim 54, wherein said talc is present in an amount of 2.3 weight percent of said coating.

56. The system of claim 12, wherein said gelatin capsule is selected from the group comprising a hard shell gelatin capsule and a soft shell gelatin capsule.

57. The system of claim 1, wherein said substantially uniform pH sensitive coating further comprising a wetting agent.

58. The system of claim 57, wherein said wetting agent is selected from the group comprising sodium lauryl sulphate, benzalkonium chloride, benzethronium chloride, docusate sodium, poloxamer, polyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, sorbitan esters or combinations thereof.

59. The system of claim 58, wherein said wetting agent is sodium lauryl sulfate.

60. The system of claim 59, wherein said sodium lauryl sulfate is present in an amount of about 2.3 weight percent of said coating.

61. The system of claim 2, wherein release of about 50 percent to about 70 percent of said minocycline from said quick release tablet occurs in less than about 90 minutes in a medium having a pH of less than about 3.9.

62. The system of claim 61, wherein said release occurs in about 60 minutes.

63. The system of claim 62, wherein said release occurs at a pH in the range of from about 1 to about 2.5.

64. The system of claim 64, wherein said release occurs in the human stomach.

65. The system of claim 1, wherein release of about 50 percent to about 70 percent of said tetracycline compound from said delayed release tablet occurs in less than about 90 minutes in a medium having a pH of from about 4 to about 7.5.

66. The system of claim 65, wherein said release occurs in the human upper intestinal tract.

67. The system of claim 66, wherein said release occurs in the duodenum/jejunum.

68. A method for the preparation of the pharmaceutical multiple tablet system of claim l, comprising using dry mix technology to prepare an effective antibacterial amount of a tetracycline compound or a non-toxic acid addition salt or a pharmaceutically acceptable salt thereof and an effective amount of at least one pharmaceutical acceptable excipient.

69. The method of claim 68 wherein said tetracycline compound is minocycline.

70. A method for the preparation of the multiple tablet system of claim 1, comprising preparing an effective antibacterial amount of a tetracycline compound or a non- toxic acid addition salt or a pharmaceutically acceptable salt thereof and an effective amount of at least one pharmaceutical acceptable excipient without using extrusion.

71. The method of claim 70, wherein said tetracycline compound comprises minocycline or a pharmaceutically acceptable salt thereof.

72. A method for the preparation of a pharmaceutical delivery system, comprising granulating an effective antibacterial amount of a tetracycline compound or a non-toxic acid addition salt or a pharmaceutically acceptable salt thereof and an effective amount of at least one pharmaceutical acceptable excipient in the presence of a granulating solution; drying; milling; optionally mixing with disintegrant, lubricant, glidant compressing said granulate to form quick release cores having diameter greater than about 3 mm; coating at least a portion of said quick release cores with a substantially uniform enteric coating to form delayed release tablets; optionally coating cores by readily erodible coating to form quick release tablets.

73. The method of claim 72, wherein said enteric coating comprises a polymer which is pH-sensitive and erodible in a medium having a pH in the range of from about 4 to about 7.5.

74. The method of claim 72, further comprising the step of at least partially filling a hard or a soft shell capsule with a pharmaceutical delivery system with a major proportion of said quick release tablets and a minor proportion of said delayed release tablets and optionally sealing said capsules.

75. The method of claim 72, wherein said tetracycline compound comprises minocycline or a pharmaceutically acceptable salt thereof.

76. A method for treating a bacterial disease, comprising administering the pharmaceutical multiple tablet system of any of claims 1 to 67 to a subject in need thereof.

77. The method of claim 76, wherein said bacterial disease is caused by bacteria selected from the group comprising as a-hemolytic streptococci, nonhemolytic streptococci, gram-negative bacilli, rickettsiae, spirochetes, Mycoplasma, and Chlamydia, including Haemophilus, Brucella, Listeria monocytogenes, Neisseria gonorrhoeae, campylobacter, Vibrio cholerae, Yersinia pestis, Bacteroides, Enterobacter, E. colt, Klebsiella, Shigella. Strep viridans group, Strep pneumonias, Strep. pyogenes, Chlamydia, Clostriduim, and Treponema pallidum.

78. The method of claim 77, wherein said bacterial disease is selected from the group comprising acne, respiratory tract infections, infections of skin, genital, and urinary systems.

79. A pharmaceutical multiple tablet system adapted to provide a therapeutically effective blood concentration level of a tetracycline compound or a pharmaceutically acceptable addition salt or a pharmaceutically acceptable salt thereof, comprising: at least one quick release tablet, comprising said tetracycline compound, an effective amount of at least one pharmaceutically acceptable excipient; and optionally a substantially uniform readily erodible coating; at least one delayed release tablet, comprising said tetracycline compound, an effective amount of at least one pharmaceutically acceptable excipient; and a substantially uniform pH sensitive coating.

80. The system of claim 79, wherein said system is adapted to provide such a concentration level for a sustained period of time of up to about twenty-four hours.

81. The system of claims 79 or 80, wherein said tetracycline compound comprises minocycline or an acceptable salt thereof.

82. The system of any of claims 78-81, characterized in that at least one of said quick release tablet and said delayed release tablet has a diameter of greater than 3 mm.

83. An encapsulated pharmaceutical system comprising two tablets, adapted to provide a therapeutically effective blood concentration level of minocycline.

84. An encapsulated pharmaceutical system comprising two tablets, wherein said system is bioequivalent to the conventional MR formulation of minocycline.

85. The system of any of claims 83 or 84, wherein said system comprises: i) at least one quick release tablet, comprising an effective antibacterial amount of said tetracycline compound or a non-toxic acid addition salt or a pharmaceutically acceptable salt thereof, an effective amount of at least one pharmaceutically acceptable excipient; and optionally a substantially uniform polymer coating; and ii) at least one delayed release tablet, comprising an effective antibacterial amount of said tetracycline compound or a non-toxic addition salt or a pharmaceutically acceptable salt thereof; an effective amount of at least one pharmaceutically acceptable excipient; and a substantially uniform pH sensitive coating, characterized in that at least one of said quick release tablet and said delayed release tablet has a diameter of greater than 3 mm.