NO177553B - Process for the preparation of a pharmaceutical dosing system - Google Patents

Description

The invention relates to a method for producing pharmaceutical dosage systems for prolonged controlled release of 7-dimethylamino-6-deoxy-6-demethyltetracycline (minocycline) or non-toxic acid addition salts thereof. It provides a dosing system that maintains therapeutic concentrations of the drug in the patient's blood for 24 hours through one daily dose of tailored formulations comprising an initial charge, or first pulse, of minocycline powder or minocycline-containing rapid-release granules, and a secondary charge , or other pulse, monocycline-containing, pH-sensitive, polymer-coated spherical granules, which are either administered simultaneously or separately with up to approx. 120 minute intervals.

These pharmaceutical dosage systems, preparations and unit forms for oral dosage will provide therapeutic plasma levels of minocycline in the therapeutic range for effective antibacterial activity for up to approx. 24 hours.

The tetracycline compound, 7-dimethylamino-6-deoxy-6-demethyltetracycline and its non-toxic acid addition salts, have extensive therapeutic applications, primarily due to their antimicrobial effects. US Patents 3,148,212 and 3,226,436 describe the preparation of minocycline. Although the compounds have achieved widespread use in oral dosage forms, they have several weaknesses.

The therapeutically effective minimum concentration level of minocycline in blood serum or plasma varies with the organism causing the infection. The concentration is determined in vivo by clinical assessment and in vitro by microbiological determinations. Currently, the therapeutically effective minimum concentration is believed to lie in the range from approx. 0.1 to approx. 1.0 µg minocycline/ml serum.

Organisms known to respond to monocycline therapy include a wide range of Gram-negative and Gram-positive bacteria including, but not limited to, rickettsiae (Rocky Mountain spotted fever, typhoid fever, and the typhoid group: Q fever, rickettsial pox , "tick fevers"); Mycoplasma pneumonia (PPLO, Eaton agent); psittacosis and ornithosis; lymphogranuloma venereum and granuloma inguinale; spirochetal microbes for "relapsing fever" (borrelia recurrentis); Lyme disease (Borrelia burgdorfeni), acne (Propionibacterium Corynebacterium acnes); the microorganisms Haemophilus ducreyi (chancroid), Yersinia pestis and Francisella tularensis, formerly Pasteurella pestis and Pasteurella tularensis, Bartonella bacilliformis, Bacteroides species, Vibrio comma, and Vibrio fetus, Brucella species, Escherichia coli, Enterobacter aerogenes (formerly Aerobacter aerogenes), Shigella species, Mima species, Herellea species, Haemophilus influenzae (respiratory tract infections), Klebsiella species (respiratory and urinary tract infections), several Streptococcus species including strains of Streptococcus pyogenes and Streptococcus faecalis, Streptococcus pneumoniae, Staphylococcus aureus (skin and soft tissue infections ), Neisseria gonorrhoeae, Neisseria meningitidis, Treponema pallidum and Treponema pertenue (syphilis and syphilis), Listeria monocytogenes, Clostridium species, Bacillus anthracis, Fusobacterium fusiforme (Vincent's infection), Actinomyces species; and in the treatment of acute intestinal amebiasis and inclusion conjunctivitis. Physician's Desk Reference, 1987, Medical Economics Company, Oradell, NJ (PDR 43rd Ed.).

Recent discoveries show that minocycline is absorbed at different rates in different parts of the gastrointestinal tract. Intubation studies in human patients have shown that the bioavailability of minocycline in the gastrointestinal tract, based on 100% absorption in the stomach, is 106% in the duodenum, 80% in the jejunum and 58% in the ileum, indicating that minocycline exhibits reduced absorption in the lower part of the gastrointestinal tract.

The human stomach is emptied in approx. 1 hour when fasting and for approx. 1 to 4 hours with food intake. The half-life of minocycline when taken without food is approx. 10 hours. Taken with food, the half-life is extended to approximately 14 to 16 hours.

It has now become possible to achieve a therapeutic blood level of minocycline by using granules of minocycline with extended release only once per day whether food is taken or not. Traditional pharmaceutical forms and traditional slow release forms containing minocycline require frequent intake of several doses per day, resulting in large variations in serum concentration during treatment and in less satisfactory patient compliance. This suggests a need for a tailored dosing system for once-daily administration of minocycline to provide optimal therapeutic effect and patient compliance.

US patent 3,080,294 mentions a pharmaceutical tablet with extended release which comprises an inner core coated with several layers of an active drug mixture, where each layer releases a portion of active drug as it successively dissolves. However, such layers are not pH adapted.

US patent 3,865,935 mentions erythromycin tablets which are stable outside the stomach, but which cause immediate action upon disintegration in the stomach. These tablets require sodium citrate or sodium citrate dihydrate and do not provide a controlled release of extended duration.

US Patent 4,138,475 shows that propranolol or a pharmaceutically acceptable salt thereof can be prepared as a sustained release preparation by mixing with a microcrystalline cellulose which is not swellable in water, which is then formed into spheres. These beads are coated with a strong film of hydroxypropylmethylcellulose and/or a plasticizer to eliminate any release of the drug into the stomach. The film-coated balls are then placed in gelatin capsules. Apart from the fact that propranolol is used as a beta-blocker to treat heart problems and not for oral antimicrobial use, there is no indication in the latter patent that the pharmaceutical preparation should be used with

tetracycline compounds.

US Patent 4,173,626 discloses capsules comprising uncoated indomethacin (US Patent 3,161,654) immediate release pellets, extended release coated indomethacin pellets, and non-drug filled pellets. Indomethacin is a prostaglandin synthetase inhibitor and is not an antibacterial agent. The covers are also not pH adjusted.

US patent 4,353,887 describes a divisible tablet containing granules, where the surface of the tablet is not increased through division.

US patent 4,606,909 describes the placement of a sparingly soluble active ingredient, such as tetracycline, in an oral dosage form with controlled release. The sparingly soluble active ingredient must be used with a dispersion-improving substance, such as an anionic surface-active agent, to accelerate solubility in the intestinal fluids. The composition is formed into small spheres and given an enteric coating to eliminate any release of the drug in the stomach. The coated balls are tableted and filled into capsules. It does not appear that such a dosage form can be used to provide a once-daily dosing system of therapeutically effective amounts of 7-dimethylamino-6-deoxy-6-demethyl-tetracycline or its non-toxic acid addition salts, or a dosing system that does not depend of nutritional intake. The necessity of a dispersion improving substance, especially an anionic surfactant, is also a negative factor.

US Patent 4,784,858 describes a controlled-release tablet comprising (1) coated cores, not necessarily spheroidized, consisting of a core of a water-soluble pharmaceutical active compound dispersed in a polymeric excipient that is not soluble in water, and a swellable polymeric substance which is not soluble in water; and (2) a coating of an elastic, water-insoluble and semi-permeable diffusion film of a polymer. In this case, water causes the core to expand so that the surface of the coating expands and becomes permeable, thereby releasing the drug in the core.

UK patent GB 2,041,222 mentions the tableting of microcapsules of indoprofen. Other active substances may also be included in the tablet. The microcapsules are not formed by spheroidization, and these tablets are only suitable for dosing high doses.

The incorporation of water-insoluble drug-containing spheres consisting of microcrystalline cellulose and at least one cellulose derivative into capsules, pads and cachets is described in UK patent GB 2,202,143. Prolonged release is achieved by the necessary mixing of the cellulose derivative.

Park-Davis has recently introduced capsules under the trademark DORYX(<R>) containing specially coated pellets of doxycycline hyclate for oral administration. See PDR 43rd. oath. (pp. 1487-1489). Unlike minocycline hydrochloride and its isomers and analogous compounds, doxycycline hyclate does not contain an alkylamino group in either the 7- or 9-position. These Park-Davis pellets are said to consist of lactose, microcrystalline cellulose and povidone (polyvinylpyrrolidone) in addition to the doxycycline compound. The description in PDR 43rd. oath. is unclear as to the benefits of using such film-coated pellets, but it is believed that the film is used to reduce release into the stomach and consequent stomach discomfort, and not to provide a dosage form intended for once-daily drug delivery.

US Patent 4,837,030 describes hard or soft gelatin capsules filled with minocycline-containing spherical granules.

It has now been discovered that a specific minocycline composition can be formulated to provide at least the minimal therapeutic serum levels of minocycline for approx. 24 hours, through two-pulse administration systems for once-daily application, comprising an initial charge component that provides the first pulse that is up to 100% absorbed in the stomach, and a secondary charge component that provides the second pulse that is absorbed up to 100% in the duodenum and in the upper part of the small intestine.

These formulations can also be included in liquids, capsules or tablets for oral administration.

Fig. 1 is a graphical illustration of a process for preparing uncoated quick-release granules and precursors of pH-sensitive polymer-coated, spherical

granules, according to the present invention.

Fig. 2 is a graphic illustration of a method for producing coated quick-release granules and pH-sensitive, polymer-coated spherical granules, according to the present invention. Fig. 3 is a graphical illustration of the release rate of minocycline from pH-sensitive polymer-coated spherical granules adapted to release minocycline in an environment having a pH of about 5.0, according to the present invention. Fig. 4 is a graphic illustration of the release rate of minocycline hydrochloride from pH-sensitive polymer-coated spherical granules adapted to release minocycline hydrochloride in an environment having a pH higher than approx. 5.5, according to the present invention. Fig. 5 is a graphic illustration of the release rate of minocycline from pH-sensitive polymer-coated spherical granules adapted to release minocycline in an environment having a pH of approx. 4.0 to approx. 7.5, according to the present invention. Fig. 6 is a graphic illustration of the release rate of minocycline from pH-sensitive polymer-coated spherical granules adapted to release minocycline in an environment having a pH of approx. 4.0 to approx. 7.5, according to the present invention. Fig. 7 is a graphical illustration of blood serum concentration levels upon once-daily administration to subjects of minocycline in oral unit dosage forms, according to the present invention and of minocycline in twice-daily oral dosage unit dosage forms of preparation from Lederle Laboratories. Fig. 8 is a graphic illustration of

the release rate of minocycline from capsules containing a mixture of quick-release granules adapted for immediate release of minocycline in the stomach, and pH-sensitive polymer-coated spherical granules adapted for minocycline release in an environment having a pH of approx. 5.0, i

according to the present invention.

Fig. 9 is a graphical illustration of the blood serum concentration levels in subjects on the 3rd day after minocycline administration once daily in oral unit dosage forms according to the present invention, and on the 3rd day of minocycline administration comprising an initial single administration of two oral unit dosage forms available from Lederle Laboratories, followed by a single oral dosage form available from Lederle Laboratories, every 12 hours (twice per day). Fig. 10 is a graphical illustration of the blood serum concentration levels in a subject on the first day of minocycline administration once per day in oral unit dosage form according to the present invention, and a single administration of two oral unit dosage forms from Lederle Laboratories. Fig. 11 is a graphic illustration of

the release rate of minocycline from capsules containing a mixture of quick-release granules adapted to release minocycline in the stomach, and pH-sensitive polymer-coated spherical granules adapted to release minocycline in an environment with a higher pH than 5.5, according to the present invention.

Fig. 12 is a graphical illustration of the blood serum concentration levels of minocycline administered to fasting and non-fasting subjects, in oral unit dosage form capsules containing a mixture of immediate-release granules adapted for intragastric release of minocycline, and pH-sensitive polymer-coated spherical granules adapted release of minocycline in an environment with a higher pH than 5.5, according to the present invention.

The method according to the invention for producing a pharmaceutical dosage system comprises the following steps:

(A) Formation of an initial charge component at

(a) comminuting 7-dimethylamino-6-deoxy-6-dimethyltetracycline, or a non-toxic acid addition salt thereof, into a fine powder; and optionally (b) mixing the powder with an effective

amount of a pharmaceutically acceptable excipient; and

(B) formation of a secondary charge component at

(a) mixing (i) an independently effective amount of at least one pharmaceutically acceptable excipient which may be the same or different from (A)(b); and (ii) an independently effective antibacterial amount of 7-dimethylamino-6-deoxy-6-demethyltetracycline, or a non-toxic acid addition salt thereof; (b) granulating the resulting mixture in the presence of a granulating liquid; (c) extruding the resulting granules; (d) spheroidizing the resulting extrudate to form precursors for coated spherical granules; (e) drying said precursors; and (f) coating the precursors with a substantially uniform polymer coating that is rapidly and substantially completely erodible in an environment having a pH in the range of 4.0 to 7.5.

Pharmaceutical preparations in oral unit dosage forms comprising a liquid may be prepared by the further step of mixing either the initial or the secondary charge component or both, either together or independently, with a pharmaceutically acceptable liquid carrier, comprising a capsule by the further step of at least partially filling a hard or soft capsule with either the initial or the secondary charge component or with both, either together or independently of each other, and optionally sealing the capsules, and comprising a tablet by the further optional step of adding a smoothing agent and the step of forming a tablet from either the initial or the secondary charge component or both, either together or independently.

The above-described pharmaceutical dosage systems and the liquid oral unit dosage forms of capsules and tablets provide once-daily controlled-release forms of minocycline that have prolonged action and maintain therapeutic blood levels for up to 24 hours, leading to desirable and effective antibacterial therapy and less frequent administration. They also counteract high local concentrations in a system that can cause side effects such as gastro-irritability.

It has thus been discovered that one can prepare new pharmaceutical dosage systems comprising mixtures or separate dosage units of an initial charge of a therapeutically effective number of coated and/or uncoated quick-release granules and a secondary charge of a therapeutically effective number of pH-sensitive polymer-coated spherical granules, mixtures or separate dosage units of an initial charge of a therapeutically effective amount of finely divided minocycline powder and a secondary charge of a therapeutically effective number of pH-sensitive polymer-coated spherical granules or multi-coated compositions. These systems and compositions can also be formed into liquid, capsule, tablet or similar oral unit dose forms. Several advantages are achieved through these new dosage systems and oral unit dosage forms compared to conventional controlled release formulations. They result in a better controlled and prolonged delivery of minocycline which in turn enables once daily dosing of 7-dimethylamino-6-deoxy-6-demethyltetracycline, or non-toxic acid addition salts thereof, to maintain a desired blood level concentration for such a relatively long time periods such as up to 24 hours. This enables less frequent administration of the minocycline compound, fewer and reduced side effects, including reduced gastro-irritability and better patient compliance.

Oral unit dosage forms are those that are administered per os and contain drugs that are absorbed into the bloodstream from the digestive tract.

An initial charge of a therapeutically effective amount of minocycline powder or number of rapid-release granules is that amount or number which provides an immediate or rapid and substantially complete release in an environment having a pH of less than 3.9 and, preferably in range from 1.0 to 2.5, such as in the stomach, thereby delivering and maintaining a recommended dosage or concentration level of 7-dimethylamino-6-deoxy-6-demethyltetracycline, or a non-toxic acid addition salt thereof, into the patient's bloodstream or plasma within a recommended period of time and maintains this level or another recommended level for another recommended period of time. This provides a first pulse of minocycline, preferably in the stomach, which rapidly approaches the therapeutic plasma level of the drug, i.e. at least the amount determined by clinical assessment in vivo or by microbiological determination in vitro, for the treatment of infections caused by invading organisms.

A secondary charge of therapeutically effective amounts of minocycline powder or number of pH-sensitive polymer-coated spherical granules is that amount or number which provides a controlled release in an environment having a pH in the range of 4.0 to 7.5, preferably from 4.0 to 6, as in the human upper intestinal tract and especially in the duodenum, thereby delivering and maintaining a further recommended dose or concentration level of 7-dimethylamino-6-deoxy-6-demethyl-tetracycline, or a non-toxic acid addition salt thereof, to the patient's blood stream or plasma within an independent, recommended period of time and maintains this level, or another recommended level, for an independent further recommended period of time. This second pulse provides a delayed release and a controlled release of minocycline, preferably in the duodenum, which extends the therapeutic plasma levels initially achieved through the first pulse, i.e. at least the amount that has been shown to be effective for the particular organism causing the infection described above, for a totally extended period of time, i.e. up to approx. 24 hours.

The initial charge of minocycline can be achieved by administering rapid-release granules containing minocycline, using a finely divided minocycline powder, using other compositions containing the minocycline compound. The secondary charge can either be administered simultaneously, as in mixtures of initial charge and secondary charge components, or sequentially after the initial charge, generally within approx. 120 minutes and preferably within approx. 60 minutes, in separate management units for initial and secondary charge components. The total time that this therapeutic plasma level is maintained, i.e. from the combined effect of the two different types of granules, from multi-coated preparations or from any other initial charge components administered simultaneously with or before the pH-sensitive polymer-coated spherical granules of the pharmaceutical dosage systems or the oral unit dose forms produced according to the present invention are preferably approx. 24 hours. A single dosage unit will therefore provide effective antimicrobial therapy for a whole day. The total therapeutic amount, i.e., the initial charge of therapeutically effective amount or number, plus the secondary charge of therapeutically effective amount, is the amount and/or number that produces and will maintain at least a therapeutically effective concentration of 7-dimethylamino-6- deoxy-6-demethyltetracycline, or a non-toxic acid addition salt thereof per ml of serum or plasma to a person for approx. 24 hours.

Salts of minocycline suitable for the present invention are non-toxic acid addition salts, e.g. sulphonic acid, trichloroacetic acid, hydrochloric acid salts.

The latter compound is also known as minocycline hydrochloride. Typical administration of minocycline hydrochloride has been as daily oral dosages of approx. 100 to approx.

400 mg in at least two, and often more, divided doses, for a normal adult. It is commercially available in many forms under the trade name Minocin(<R>) from Lederle

Laboratories - Wayne, New Jersey (PDR 43rd Ed.).

It should also be noted that minocycline hydrochloride

readily undergoes epimerization and oxidative degradation to epiminocycline, a pharmacologically inactive and undesirable tetracycline compound. The amount of the epimer should be as small as possible, but can amount to as much as from 1.5% to 10% without affecting the intended daily dosage according to the present invention.

The pharmaceutical dosage systems and oral unit dosage forms will preferably contain from 25 mg to 400 mg, preferably from 80 mg to 280 mg, of 7-dimethylamino-6-deoxy-6-dimethyltetracycline, or non-toxic acid addition salts thereof. Preferably, the ratio between the initial charge component, i.e. minocycline powder, quick-release granules, quick-release coating or the like, and the secondary charge component, i.e. pH-sensitive polymer-coated spherical granules or single-coated cores, ranges from 20:80 to 80 :20 parts by weight of the combined weight of initial and secondary charge components, preferably from 30:70 to 70:30. Preferably, the initial charge component, the secondary charge component or both contain from 20 to 200 mg of minocycline.

The rapid and almost complete release of the initial charge component is such that the initial charge component releases more than 70%, and preferably more than 80% of the minocycline content in less than 90 minutes and preferably less than 60 minutes in an aqueous buffer environment, e.g. hydrochloric acid and/or acetate buffer with a pH of less than 3.9.

The rapid and substantially complete release of the secondary charge component or single coated core is such that the secondary charge component or single coated core releases more than 50% and preferably more than 70% of the minocycline amount in less than 90 minutes in an aqueous buffer environment, e.g. acetate and/or phosphate buffer, which has a pH in the range from 4.0 to 7.5. The pH-sensitive polymer coating must therefore be rapidly and almost completely erodible or soluble to allow the secondary charge component or single coated core to meet these conditions.

Other preferred embodiments of dosage systems produced according to the present invention also cause from 5 to 20% of the minocycline amount in the secondary charge component or single coated core to be released in approx. 2 hours by suspension in an environment of simulated gastric juice which has a pH of approx. 1.2 at approx. 37°C or from 20 to 50% of the minocycline amount in the secondary charge component or single coated core, is released in approx. 2 hours when suspended in an environment of simulated gastric juice which has a pH of approx. 1.2 at approx. 37°C.

The medication is released when it can be determined using a standard method. Many pharmaceutical excipients will be suitable for use according to the present invention. An excipient with known solubility and swellability in gastric juice and juice from the upper small intestine, especially the duodenum, should be used. Such excipients either in the quick-release granules, the pH-sensitive polymer-coated spherical granules, the cores or combinations thereof, include lactose, other mono- or disaccharides, microcrystalline cellulose, starch, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, croscarmellose sodium, pregelatinized starch, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, hydroxypropylmethylcellulose, cellulose acetate, hydroxypropylmethylcellulose phthalate, polyvinylacetate phthalate, microcrystalline cellulose in combination with lactose, microcrystalline cellulose in combination with sodium carboxymethylcellulose, microcrystalline cellulose in combination with croscarmellose sodium, mixtures thereof and the like, as for example indicated in Remington's Pharmaceutical Sciences, 1985, 17th Edition, Philadelphia College of Pharmacy and Science, Chapter 68, Pharmaceutical Necessities, pages 1278-1320.

Although a single excipient can be used, e.g. microcrystalline cellulose, desirable results may require more careful selection of an appropriate amount of minocycline for use in the beads. Combinations of more than one excipient may therefore be desirable.

. Suitable forms of microcrystalline cellulose are, for example, products marketed as Avicel^<R>^ PH-101 and Avicel<<R>) PH-105 (from FMC Corporation - American Viscoe Division, Avicel Sales, Marcus Hooks, PA, U.S.A.) Avicel<R) PH-101 is characterized by having an average particle size of 50 µm, particle size specification of

+60 mesh, less than 1%, and 2 00 mesh less than or equal to 30.0%, moisture content of less than 5.0% and acceptable flow properties. Avicel<<R>) PH-105 has an average particle size of 20 jum, particle size specification of 400 mesh less than or equal to 1.0%, moisture content of less than 1.0% and poor flow properties.

A suitable mixture of microcrystalline cellulose and sodium carboxymethyl cellulose is, for example, the product sold as Avicel(<R>) RC-581 from FMC Corporation. Avicel(<R>) RC-581 is characterized by an average particle size of less than 0.2 micron, particle size specification of 60 mesh less than or equal to 0.1% and moisture content of less than 6%.

By the term "spheres" is meant here spherical granules having a diameter in the range from 0.1 to 2.5 mm, preferably from 0.5 to 2 mm and most preferably from 0.8 to 1.2 mm. Preferably, the quick-release granules are also spherical. If spheres are to be produced that have the drug as a surface layer, coated germs can be used, e.g. non-pareil chimeras or sugar crystals. Such non-pareil germs generally have a size of 0.1 mm to 2.0 mm, typically approx. 1.0 mm. They can, for example, consist of a mixture of sugar and starch. Such crystals generally have a size of 0.01 mm to 0.1 mm.

The quick-release granules are usually uncoated. However, they can optionally be coated with a polymer coating which is fast and almost completely erodible in an environment with a pH of less than approx. 3.9, especially in the stomach, whereby their immediate and rapid release characteristics remain relatively unchanged.

The polymer coating of the coated spherical granules is pH-sensitive and is rapidly and almost completely erodible in an environment that has a pH in the range from 4.0 to 7.5, especially in the upper small intestine and especially in the duodenum, whereby erosion at pH outside this area, e.g. in the stomach, is hindered, while the rapid, controlled release characteristics of the coated spherical granules remain unaffected after the polymer coating is eroded in the upper part of the small intestine, i.e. the duodenum.

This pH-sensitive film-forming polymer can also vary significantly in type and amount as related to film or coating thickness.

Illustrative, but not limiting, pH-sensitive coating polymers are methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, hydroxypropylmethylcellulose succinate, a polymer or copolymer of (meth)acrylic acid or (meth)acrylic acid methyl ester, polyvinyl acetate phthalate or polymers or copolymers of polyvinyl acetate, cellulose acetate , fatty acids and esters thereof, cellulose acetate trimellitate and mixtures thereof, calculated to dissolve completely in an environment having a pH of from 4.0 to 7.5, preferably from 4.0 to 6. These coatings may further include any of the conventional additives mentioned above.

Commercial coating compositions that have proven suitable include Eudragit(<R>) (Rohm Pharma, Westerstadt, Germany), Surelease(<R>) (Colorcon Inc., West Point, PA), Aquacoat(<R>), (FMC Corp .), Coateric(<R>) (Colorcon Inc.), Aquateric<<R>) (FMC Corp.), Eastman(<R>) C-A-P™ (Eastman Kodak Company) and Eastman-C-A-T (Eastman Kodak Company). A suitable ethyl cellulose has a viscosity in the range from 5 to 100 eps at 20°C (US National Formulary XIII) (the content of ethoxy groups 44 to 51 percent by weight) and in particular a viscosity of 50 eps at 20°C (the content of ethoxy groups 48 to 49 percent by weight) ). A suitable hydroxypropylmethylcellulose has a viscosity in the range of 3 to 100 eps at 100°C (US National Formulary XIII), particularly a viscosity of 6 eps at 20°C. Preferred coatings are hydroxypropylmethylcellulose phthalate or a combination of hydroxypropylmethylcellulose phthalate and hydroxypropylmethylcellulose, and ideally these coatings should dissolve almost completely in an environment having a pH of 5.0 or higher, e.g. higher than 5.5.

Although a weight increase of from 5 to 35 parts by weight based on the weight of the uncoated spherical granules (precursors of coated spherical granules) is suitable, a weight increase of from 5 to 25 parts by weight is preferred, especially 10 to 25 parts by weight.

The polymer coating can also include a substrate, a cover layer or a combination of these. To achieve the best results, an increase in weight of 1 to 10 parts by weight in addition to the standard coating is preferred when an aqueous formulation is used.

The amounts of minocycline and excipient comprising the quick-release granules can vary considerably but will generally be in the range from 10 to 70 parts by weight of minocycline and from 90 to 30 parts by weight of excipient, based on 100 parts by weight of minocycline and excipient in total. Preferably, the quick-release granules comprise approx. 50 parts by weight minocycline and approx. 50 parts by weight excipient, based on 100 parts by weight -minocycline and excipient in total.

The amount of minocycline and excipient constituting the precursors for the pH-sensitive polymer-coated spherical granules can also vary considerably, but will generally be in the range of from 10 to 90 parts by weight of minoccyline and from 90 to 20 parts by weight of excipient, based on 100 parts by weight of minocycline and excipient in total . The amount of pH-sensitive polymer coating on the precursors also varies considerably, and these are described above. Preferably, the coated spherical granules or cores will consist of approx. 60 parts by weight minocycline and approx. 40 parts by weight auxiliary substance, based on 100 parts by weight minocycline and auxiliary substance in total, and the pH-sensitive polymer coating includes a weight increase of approx. 10 to approx. 25 parts by weight based on 100 parts by weight of minocycline and excipients in total.

The amount of rapid-release granules or initial charge component and the amount of pH-sensitive polymer-coated spherical granules or secondary charge component in pharmaceutical dosage systems, oral unit dosage forms or multi-coated compositions will vary considerably, but will generally range from 20 to 80 parts by weight of rapid -release granules or initial charge component and 80 to 20 parts by weight of pH-sensitive polymer-coated spherical granules or secondary charge components, based on 100 parts by weight of quick-release granules or initial charge components and pH-sensitive polymer-coated spherical granules or secondary charge components in total. Preferably, the quick-release granules or the initial charge component comprise from 30 to 70 parts by weight and the pH-sensitive polymer-coated spherical granules or secondary charge components from 70 to 30 parts by weight, based on 100 parts by weight of the quick-release granules or initial charge component and the pH-sensitive polymer-coated spherical granules, single coated cores or secondary charge components altogether.

The initial charge and/or the secondary charge components in the pharmaceutical dosage systems can be mixed individually or in combination, independently of each other, with a known pharmaceutically acceptable liquid carrier, such as diluents, emulsifiers and suspending agents, possibly together with additional active substances, dyes, pigments, flavorings, additional excipients or a combination of these to provide an oral unit dosage form.

The components of the pharmaceutical dosing systems can also be filled separately or in combination into hard or soft gelatin capsules, possibly together with additional active substances, smoothing agents, disintegrants, plasticizers, dyes, pigments, aroma substances, additional excipients or a combination of these, using any conventional capsule forming and/or filling machine and optionally sealed in a known manner by e.g. spot welding, by gelatin bands with adapted locking rings.

The hard gelatin capsules used in this context are generally composed of gelatin, water and possibly FD&C dyes, opacifying agents such as titanium oxide, sulfur dioxide to prevent decomposition, or a combination of these. They generally consist of two sections, one of which slides over the other, completely surrounding the content.

The soft capsules generally consist of a soft, spherical gelatin shell which is somewhat thicker than the shell in the hard capsules. The gelatin is usually softened by the addition of glycerol, sorbitol or a similar polyol. They may also contain a preservative to prevent fungal growth.

The components in the pharmaceutical dosage systems can also be individually or in combination, shaped as such, or smoothing agents, disintegrants, plasticizers, dyes, pigments, flavoring substances, additional active substances, pharmaceutically acceptable excipients or a combination of these can be added to tablets of oral unit dosage forms in a conventional way, e.g. by compression or pressing. The tablets can then optionally be coated with a cover layer as explained above.

All pharmaceutical dosage systems, compositions or oral unit dosage forms can be prepared using conventional pharmaceutical production equipment.

Fig. 1 illustrates the typical steps in the preparation of uncoated spherical granules for use either as uncoated quick-release granules or as precursors for pH-sensitive polymer-coated spherical granules. In the first instance, an effective amount of at least one pharmaceutically acceptable excipient and an effective antibacterial amount of 7-dimethylamino-6-deoxy-6-demethyltetracycline, or a non-toxic acid addition salt thereof, are mixed in a mixing apparatus. The resulting mixture from the first step is granulated with a liquid medium, e.g. an aqueous solution or an organic solvent, and preferably water, until the appropriate consistency for extrusion is obtained. The resulting granulated mass is then extruded in an extruder or extruder/spheroidizer, through a suitably sized, e.g. 1.0 mm, perforated plate and spheroidized at high speed for sufficient time to form spherical granules. The moist spherical granules are then dried in conventional equipment at suitable temperatures, e.g. drying in trays at 55 to 65°C or in a conventional fluid bed drying system at 65 to 70°C, to a low moisture level, e.g. 1 to 7%, preferably 2 to 5%.

Fig. 2 illustrates that the spherical granules are coated with an almost uniform polymer coating which is fast and almost completely erodible in an environment that has a pH from approx. 4.0 to approx. 7.5, in a similar way as above.

An initial charge of a therapeutically effective number of uncoated immediate-release granules or an initial charge of a therapeutically effective amount of minocycline, or a combination thereof, may then be mixed in a slow-moving blade mixer with a secondary charge of a therapeutically effective number pH-sensitive polymer-coated spherical granules.

The mixture or separate units of initial and secondary charge components may then optionally be mixed with a pharmaceutically acceptable liquid carrier.

Alternatively, a hard capsule or soft capsule can be at least partially filled and optionally sealed as described previously, to form an oral capsule of unit dosage form.

Tableted unit dosage forms for oral use can be prepared by possibly adding a smoothing agent or another pharmaceutically acceptable excipient and subsequent compression or pressing.

The pharmaceutical dosage systems, spherical pharmaceutical compositions or oral unit dosage forms containing these can be administered by swallowing, whereby a therapeutic level of minocycline is maintained in the blood stream of a warm-blooded mammal, for about 24 hours and thereby for approx. 24 hours provides a therapeutic blood level using a once-daily dosing system.

The following examples illustrate the invention. Parts are expressed by weight unless otherwise stated. Bioavailability is a function of, and is an absolute term that indicates the measurement of, both the true rate and the total amount of drug from an administered dosage form that reaches the bloodstream.

Example 1

A mixture is prepared by mixing 2500 g of minocycline hydrochloride powder (Minocin<*R>) - Lederle Laboratories) and 2500 g of microcrystalline cellulose (Avicel(<R>) PH-101, FMC Corporation) in a Hobart mixer with low speed. The powder mixture is then granulated to an extrudable consistency by slowly adding and mixing in 300 ml of water. The resulting granules are extruded at high speed through a 1.0 mm plate in a NICA Extruder/Spheroidizer Model S450, and then spheroidized at high speed. The moist balls are dried in an Aeromatic fluid bed dryer by supplying 70°C air until the moisture content is approx. 1 to 7% to form uncoated quick-release granules having a smooth surface and a homogeneous distribution of the tetracycline compound.

Example 2

A mixture is prepared by mixing 3000 g minocycline hydrochloride powder (Minocin^<R>) - Lederle Laboratories), 1650 g microcrystalline cellulose (Avicel(<R>) PH101, FMC Corporation) and 350 g AC-DI-SOL ( crosscarmellose sodium) in a Hobart mixer at low speed. The powder mixture is then granulated to an extrudable consistency by slowly adding 300 ml of water and mixing. The resulting granules are extruded at high speed through a 1.0 mm plate in a NICA Extruder/Spheroidizer Model S450 and spheroidized at high speed. The moist balls are dried in an Aeromatic fluid bed dryer at 70°C inlet air until the moisture content is approx. 1 to 7% to form precursors for coated spherical granules.

A pH-sensitive polymer coating that is soluble in an environment with a pH of approx. 5.0 is prepared by mixing 75 parts of hydroxypropylmethylcellulose phthalate (HP-50, Shin-Etsu Chemical, Tokyo, Japan) calculated to dissolve in an environment having a pH of approx. 5.0, 15 parts mineral oil and 10 parts orange dye (Opaspray K-1-2562, Colorcon, Inc., West Point, PA) and dissolve the mixture in an organic solvent.

The polymer coating solution is sprayed onto 900 g of dried precursors for coated spherical granules at an initial rate of 7 ml/min, which is gradually increased to 9 ml/min. in a Uni-Glatt Model 82/E fluidized bed until a weight gain of 16 parts is obtained, calculated on the basis of the weight of the coated spherical granule precursors. The inlet air temperature is regulated to 54°C, while the outlet air is regulated to between 22 and 25°C.

Here, pH-sensitive polymer-coated spherical granules are formed, which have a polymer coating that erodes quickly and practically completely in an environment with a pH of approx. 5.0.

Dissolution profiles of the minocycline hydrochloride are determined by USP XXI test methods using dissolution media of simulated gastric juice with a pH of 1.2, of buffered media with pH of 4.5 and 6.0, and a simulated intestinal fluid with a pH of 7.2. The results are shown graphically in Fig. 2.

Example 3

The procedure in Example 2 is followed, but before the pH-sensitive polymer coating is applied to the precursors for coated spherical granules, a substrate of hydroxypropylmethylcellulose is applied by spraying until a weight increase of approx. 1 to approx. 5 parts, based on the weight of the precursors are obtained. This gives the precursors a smooth surface for later application of a pH-sensitive polymer coating.

Example 4

Coated spherical granules are produced according to the method in Example 2. Then a covering layer of hydroxypropylmethylcellulose is applied until a weight increase of approx. 1 to approx. 5 parts, based on the weight of the precursors for coated spherical granules are obtained.

Example 5

pH-sensitive polymer-coated spherical granules with a substrate are produced according to the method in Example 3. Then a cover layer of hydroxypropylmethylcellulose is applied by spraying until a weight increase of approx. 1 to approx. 5 parts by weight, based on the weight of precursors with a substrate, but without a cover layer.

Example 6

The procedure in Example 2 is followed by using a pH-sensitive polymer coating which is soluble at a higher pH than approx. 5.5, and which is prepared by mixing 75 parts of hydroxypropylmethylcellulose phthalate (HP-55, Shin-Etsu Chemical, Tokyo, Japan) intended for dissolution in an environment having a pH of more than approx. 5.5, 15 parts mineral oil and 10 parts orange dye (Opaspray K-1-2562, Colorcon, Inc.) and dissolve the mixture in an organic solvent.

Dissolution profiles of the minocycline hydrochloride are determined by USP XXI test methods using dissolution media of simulated gastric juice with a pH of 1.2, of buffered media with pH of 4.5 and 6.0, and a simulated intestinal fluid with a pH of 7.2. The results are shown graphically in Fig. 4.

Example 7

The procedure in Example 2 is followed, but by using a pH-sensitive polymer coating which is soluble in an environment with a pH from 4.0 to 7.5, which is prepared by mixing 71.25 parts of hydroxypropylmethylcellulose phthalate (HPMCP-50, Shin-Etsu Chemical, Tokyo, Japan), 3.75 parts

hydroxypropyl methyl cellulose (Shin-Etsu Chemical), 15 parts mineral oil and 10 parts orange dye (Opaspray K-1-2562, • Colorcon, Inc.) dissolve the mixture in an organic solvent and apply the polymer solution as a spary up to a weight gain of 10 parts by weight based on the weight of coated spherical granules.

The dissolution profiles of minocycline hydrochloride are determined by USP I test methods using dissolution environments of simulated gastric juice with a pH of 1.2, of buffered media with pH of 4.5 and 6.0 and a simulated small intestinal fluid with a pH of 7.2. The results are shown graphically in Fig. 5.

Example 8

The procedure in Example 7 is followed, except that the pH-sensitive polymer coating is applied until a weight increase of 20 parts by weight based on the weight of the cores for coated spherical granules is achieved.

Example 9

The procedure in Example 2 is followed, but with a pH-sensitive polymer coating which is soluble in an environment with a pH from approx. 4.0 to approx. 7.5, which is prepared by mixing 60 parts of hydroxypropylmethylcellulose phthalate (PMCP-50, Shin-Etsu Chemical, Tokyo, Japan), 15 parts of hydroxypropylmethylcellulose (Shin-Etsu Chemical), 15 parts of mineral oil and 10 parts of orange dye (Opaspray K-l- 2562, Colorcon, Inc.), dissolve the mixture in an organic solvent and spray the polymer coating solution until a weight gain of 10 parts by weight, based on the weight of the coated spherical granule precursors, is achieved.

Example 10

The procedure of Example 9 is followed, except that the pH-sensitive polymer coating is applied until a weight gain of 20 parts by weight is achieved based on the weight of the coated spherical granule precursors.

Dissolution profiles of minocycline hydrochloride are determined by USP XXI test methods using buffered media with pH values of 4.0, 4.5 and 6.0.

The results are shown graphically in Fig. 6.

Example 11

pH-sensitive polymer-coated spherical granules are prepared according to the method of Example 2. The resulting coated spherical granules are mixed with a pharmaceutically acceptable liquid medium to provide a unit dosage form for oral use.

Example 12

pH-sensitive polymer-coated spherical granules are prepared according to the procedure in Example 2. The resulting coated spherical granules are filled into hard capsules to provide a unit dosage form for oral use.

Example 13

pH-sensitive polymer-coated spherical granules are prepared according to the procedure in Example 2. The resulting coated spherical granules are filled into soft capsules to provide a unit dosage form for oral use.

Example 14

pH-sensitive polymer-coated spherical granules are prepared according to the procedure of Example 2. The resulting coated spherical granules are pressed into a tablet to provide a unit dosage form for oral use.

Example 15

The procedure in Example 2 is followed, but with an anionic polymerizate of methacrylic acid and methyl methacrylate (Eudragit(<R>) - Rhom Pharma) instead of the pH-sensitive polymer coating to form pH-sensitive polymer-coated spherical granules.

A 185 mg sample of minocycline hydrochloride prepared according to the procedure of Example 16 is administered to a subject and the serum concentration levels of minocycline hydrochloride are measured over a 24 hour period. The result is shown in Fig. 7 in the curve indicated by "Example 15". The results show that without a rapid-release initial loading dose of minocycline, blood levels of minocycline fall below the minimally therapeutically effective amounts desired in most minocycline therapies, after approx. 10-12 hours.

Example 16

690 g of quick-release granules prepared according to the method of Example 1, and 810 g of the pH-sensitive polymer-coated spherical granules prepared according to the method of Example 2, are mixed in a low shear blender at low speed for 15 minutes to form a spheroidized pharmaceutical preparation mixture.

Example 17

The mixture prepared according to the method of Example 16 is mixed with a pharmaceutically acceptable liquid carrier to form oral unit dosage forms having a total minocycline content of 185 mg, where 85 mg of the minocycline content is included in the rapid-release granules and 100 mg of the tetracycline compound included in the pH-sensitive polymer-coated spherical granules.

Example 18

The mixture prepared according to the procedure of Example 16 is filled into hard gelatin capsules to form oral unit dosage forms having a total minocycline content of

185 mg, where 85 mg of the minocycline content is included in the quick-release granules and 100 mg of the tetracycline compound is included in the pH-sensitive polymer-coated spherical granules.

Dissolution profiles of minocycline are determined by U.S.P. XXI test methods using dissolution media with pH of 1.2 and 7.2. The results are shown graphically in Fig. 8.

The serum concentration levels of minocycline over the first 12 hour period are also shown in Fig. 10 of the curve labeled "Example 18".

The once-per-day regimen is maintained for 3 days, and serum concentration levels for the 24-hour period beginning with the start of Day 3 are measured over the subsequent 24-hour period. The results are shown in Fig. 9 in the curve labeled "Example 18".

Comparative example 18A*

Two capsules each containing 100 mg of minocycline hydrochloride powder (Minocin(<R>) - Lederle Laboratories) are given as a loading dose to a subject. For the following 3 days, a capsule containing 100 mg of minocycline hydrochloride powder (Minocin<*R>)) is given every 12 hours.

Serum concentration levels are measured over the first 12 hour period after administration. The results appear from

Fig. 10 in the curve designated "Comparative example 18A*".

The serum concentration levels for the 24-hour period beginning with the start of day 3 are measured over the following 24-hour period. The results appear in Fig. 9 in the curve labeled "Comparative example 18A*".

Example 19

The mixture prepared according to the procedure in Example 16 is pressed into tablets to provide oral unit dosage forms having a total minocycline content of 185 mg, where 85 mg of the minocycline content is included in the rapid-release granules and 100 mg of the tetracycline compound is included in the pH- sensitive polymer-coated spherical granules.

Example 2 0

690 g of the quick-release granules prepared according to the method of Example 1, and 810 g of the pH-sensitive polymer-coated spherical granules prepared according to the method of Example 6, are mixed in a knife blender at low speed for 15 minutes to form a spheroidized pharmaceutical preparation mixture .

Example 21

The mixture prepared according to the procedure of Example 20 is filled into hard gelatin capsules to form oral unit dosage forms having a total minocycline content of

185 mg, where 85 mg of the minocycline content is included in the quick-release granules and 100 mg of

the tetracycline compound is included in the pH-sensitive polymer-coated spherical granules.

Bioavailability is determined to be 76% by measuring the area under the plasma concentration curve and comparing this with the area under a reference curve from Comparative Example 2 IA*.

Dissolution profiles of minocycline are determined by U.S.P. XXI test methods using dissolution media with pH of 1.2 and 7.2. The results are shown graphically in Fig. 11.

A capsule is given to a subject, and

the serum concentration levels of minocycline are measured over a 24-hour period. The results appear in Fig. 7 in the curve labeled "Example 21". A maximum minocycline serum concentration of 1.9 µg/ml serum is reached after 3.8 hours.

A capsule is given to both a fasting subject and one who eats regularly. The serum concentration levels of the tetracycline compound are measured over a 24-hour period. The results showing that minocycline plasma concentration levels remain at more than the therapeutically effective minimum serum concentration for more than approx. 24 hours, is shown in graphic form in Fig. 12.

Comparative example 2IA*

A capsule containing 100 mg of minocycline hydrochloride powder (Minocin(<R>) - Lederle Laboratories) is given to a subject, after which serum concentration levels of minocycline hydrochloride are measured over a 12-hour period. A new capsule containing 100 mg of minocycline hydrochloride powder (Minocin^<R>) is given at the end of the 12-hour period, and minocycline hydrochloride serum concentration levels are measured over the next 12-hour period. The results appear in Fig. 7 in the curve labeled "Comparison example 21A<*>".

The bioavailability is set to 100% as this is the comparison reference.

A peak serum concentration of minocycline hydrochloride during the first 12-hour period of 1.78 ug/ml serum is achieved at 1.5 hours, and a peak serum concentration of minocycline hydrochloride during the second 12-hour period of 2, 65 µg/ml is reached 1.8 hours after administration of the second capsule. Minocycline hydrochloride plasma level concentrations exhibiting wide fluctuations may result in undesirable side effects such as nausea and gastro-irritability.

Examples 2 (Fig. 3), 6 (Fig. 4), 7 (Fig. 5) and 10 (Fig. 6) demonstrate the selective release properties of the pH-sensitive polymer-coated spherical granules.

Example 21 shows the ability of the compositions and oral unit dosage forms produced according to the present invention to maintain a further prolonged and better controlled release of minocycline, and thus the ability to provide a relatively uniform, at least therapeutic minimum concentration level of minocycline in the blood in up to 24 hours when administered only once per day.

Comparative Examples 18A* and 2IA* illustrate the nonuniform release rate and large fluctuations in minocycline blood levels that result from conventional mincocycline dosages.

Example 21 also shows that the extended controlled release properties are also maintained in a fasting patient, thereby eliminating the need for regular food intake to achieve a therapeutic effect.

Example 18 also shows that the extended controlled release properties of the unit dosage forms prepared according to the present invention are maintained even after 3 days of continuous administration and that continuous use does not impair their extended controlled

release properties.

Comparative example 18A*, on the other hand, shows that traditional dosage forms of minocycline, even after 3 days of administration, still provide uneven release with large blood level fluctuations and can consequently result in unwanted side effects.

Comparative Examples 18A* and 2IA* further illustrate that conventional oral unit dosage forms are unable to maintain therapeutic minimum concentration levels over extended periods of time. The effect of the initial dose decreases rapidly after approx. 12 hours, which is evident from the relatively weak increases above the initial concentration that are achieved after administration of a new dose after approx. 12 hours.

Comparative example 18A* illustrates, in relation to Examples 18 and 21, that the relatively low dosages according to the present invention provide relatively even therapeutically effective concentration levels of minocycline.

Examples 19 and 21 demonstrate the pH-sensitive properties of preparations and oral unit dosage forms according to the present invention.

All patents, applications, publications and test methods mentioned above are hereby incorporated into the present description with their entire contents.

Claims (1)

Method for manufacturing a pharmaceutical dosage system, characterized by the following step (A) forming an initial charge component by (a) comminuting 7-dimethylamino-6-deoxy-6-demethyl-tetracycline, or a non-toxic acid addition salt thereof, to a fine powder; and optionally (b) mixing the powder with an effective amount of a pharmaceutically acceptable excipient; and (B) forming a secondary charge component by (a) mixing (i) an independent amount of at least one pharmaceutically acceptable excipient which may be the same or different from (A)(b); and (ii) an independently effective antibacterial amount of 7-dimethylamino-6-deoxy-6-demethyltetracycline, or a non-toxic acid addition salt thereof; (b) granulating the resulting mixture in the presence of a granulating liquid; (c) extruding the resulting granules; (d) spheroidizing the resulting extrudate to form precursors for coated spherical granules; (e) drying said precursors; and (f) coating the precursors with an approximately uniform polymer coating, which is rapidly and approximately completely erodible in an environment having a pH in the range of 4.0 to 7.5.