GB2420708A

GB2420708A - Tetracycline controlled release pharmaceutical composition

Info

Publication number: GB2420708A
Application number: GB0524368A
Authority: GB
Inventors: Paul Anthony Fleming
Original assignee: Alpharma Ltd
Current assignee: Accord UK Ltd
Priority date: 2003-09-30
Filing date: 2004-09-30
Publication date: 2006-06-07
Also published as: GB2406517A; GB0524368D0; GB0322848D0; GB2406517B; GB0421759D0

Abstract

A controlled release dosage form comprising a tetracycline, excipient and polymer, especially a capsule containing pellets of minocycline, glycerol monostearate, cellulose and polyvinyl pyrrolidone.

Description

2420708: :

S S S S S S I S

S Sf5 7!? III TETRACYCLIrE CONTROLLED RELEASE PEARMACEUTIC,

COMPOSITION

FIELD OF THE INVENTION

This invention is concerned with a pharmaceutjcai composition for the controlled release of antibacterial agents comprising tetracycline compounds. More specifically it is concerned with pellets comprising a tetracycline compound blended with an excipient, the pellets being forffiulated to control the rate of release of the tetracycline in the human stomach and human intestine upon oral administration, in order to achieve an optimal blood level. When the pellets are filled into capsules or compressed into tablets, and the like, there are provided controlled release dosage forms of tetracycline compounds.

BACKGRO OF THE INVENTION

Tetracycline compounds are widely used in therapy primarily for their antimicrobial effect. A pref erred family of such agents comprises the 7or 9-alkylamino-6- including the non-toxic 25 acid-addition salts thereof.

In Bechgaard, U.S. 4,606,909, the placement of a sparingly soluble active substance, such as tetracycline, in an oral controlled release dosage form is disclosed.

The sparingly soluble active substance must be used with a dispersionenhancing substance, such as an anionic detergent to promote Solubility in intestinal fluids. The composition is formed into small spheres and enteric coated to eliminate any release of drug in the stomach.

The coated spheres are tabletted or loaded into capsules.

The requirement to use a dispersion-enhancing substance, a. . - 4 4. * * *. i * 4 * I I 4 4 * S S S S * I I 4 4 2. III 441 III especially an anionic detergent, is a negative factor.

In EP 310 814 B1, spheronized spheres containing minocycljne HC1 are made by mixing minocycline with microcrystalline cellulose followed by spheronization, and are thereby stated to be adapted to retard the rate of release of the tetracycline compound in the human stomach and to promote rapid release of said tetracycline compound in the human intestine upon administration.

However, in order to achieve the desired dissolution profile, the teaching is that coating of the pellets is necessary.

StJIAMARY OF THE INVENTION A need still exists for an improved controlled release tetracycline containing composition, especially one without coatings such as film coatings, and especially capsules which confers controlled release even though the capsule only contains one type of pellet. The above objective has been met by the present invention in a way not suggested in the foregoing prior art. The composition of the present invention is formulated to control release on oral administration. Preferably, it will have a prolonged release of the tetracycline compound compared to a traditional formulation.

This is accomplished by preparing a composition, e.g. in the form of pellets, containing the tetracycline with at least one excipient and at least one polymer giving the composition the unexpected and advantageous properties.

According to the present invention there is provided a pharmaceutical composition which comprises 3-5 (I) a tetracycline compound or a non-toxic acid addition salt thereof; a. I * . a a,t I I * a a a I * * I * * * * V V * as. 555 II.

(II) at least one pharmaceutically acceptable excipient selected from the group consisting of waxes; fats; esters of fatty acids with polyols; monoglycerides; diglycerides; and triglycerides said excipient (or excipients) being present in an amount of 8-35%- of the amount of the tetracycline (w/w); and (III) at least one polymer selected from the group Consisting of: microcrystalline cellulose; polyviny1pyrrolj. hydroxypropylmethyi cellulose; methy1celu05. ethylcellulose; hydroxyethyl cellulose; hydroxypropyl cellulose; hydroxypropyl methylcellulose phthalate; cellulose acetate phthalate; hydroxypropyl methylcellulose succinate; a polymer or copolymer of (meth)acrylic acid or an ester thereof; and sodium carboxymethy1..cel05 said polymer (or polymers) being present in an amount of 20-100%- of the amount of the tetracycline (w/w).

Also provided is a pharmaceutical composition in the form of a plurality of pellets and a capsule filled with a plurality of said pellets as well as a process for the preparation of the composition.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a pharmaceutical composition which comprises a tetracycline compound or a non-toxic acid addition salt thereof and at least one pharmaceutically acceptable excipient selected from the group consisting of waxes; fats; esters of fatty acids with polyols; monoglycerides; diglycericles; triglycerides; and mixtures thereof, said excipient (or excipients belonging to said group) being present in an amount of 8-35% of the amount of the tetracycline (w/w). S a a

* * a a * a * p 5 * , a * * a a * a S P * S.. iS a.. a The excipient has preferably a melting temperature above 25 C, and more preferably above 40 C, such as above 50 C, above 60 C or above 70 C. An excipient of this kind can found in the group comprising mono, di or tn-esters of glycerol with a saturated fatty acid having more than 10 carbon atoms, more preferably 16 or more, e.g. 18 C atoms. it is presently preferred to use an ester of glycerol with steanic acid, such as glycerol monostearate The pharmaceutical composition according to the invention further comprises a polymer selected from the group consisting of: microcrystalline cellulose; polyvinylpyrrol idone; hydroxypropylmethyl cellulose; methylce11u1os; ethylcellulose; hydroxyethyl cellulose; hydroxypropyi cellulose; hydroxypropy]. methylcellulose phthalate; cellulose acetate phthalate; hydroxypropyl methy1celiu].os succinate; a polymer or copolymer of (meth)acrylic acid or an ester thereof; sodium carboxymethy1....celi05 or a mixture thereof.

Examples on pref erred embodiments of the pharmaceutical composition is a composition which comprises a tetracycline compound or a non-toxic acid addition salt thereof and, measured relative to the weight of tetracycline (such as minocycline) (w/w), 8-35 of an excipient as defined in claim 1 and 20-100 of polymers, a pharmaceutical composition which comprises minocycline hydrochloride and, measured relative to the weight of minocycline (w/w), 8-356 glycerol monostearate and 20- polymers, and a pharmaceutical composition which comprises minocycline hydrochloride and, measured relative to the weight of minocycline (w/w), l0-30 glycerol monostearate, 20-60 microcrystalline cellulose and 3-l5% polyvinyl pyrrolidone. It should be understood that if a dosage form comprises ioo mg tetracycline compound, it should further comprise e.g. 10-30 mg 8 4 * * - - * * , * - S I I II * . I * *q rS 554 I *

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glycerol monostearate 20-60 mg microcrystalline cellulose and 3-15 mg polyvinyl pyrrolidone. It is presently preferred that the composition comprises, relative to the weight of the tetracycline (w/w), 10-30% (such as 12-28%, 14-25%, or 16-20%), of the above excipient(s) 20-80% (such as 25-70%, 30-60% or 35-55%) of the polymer or mixtures of polymers. Especially, it is preferred that the composition comprises 20-60% (such as 30-50% or 35-45%) cellulose (eg. microcrystalline) and 3- 14% (such as 4-12%, 5-10% or 6-9%) A pref erred pharmaceutical composition therefore comprises 55-65%wt minocycline hydrochloride 9-12 %wt glycerol monostearate, 22-27 %wt microcrystalline cellulose, and 3-6 %wt povidone.

In an interesting embodiment, the form of the pharmaceutical composition is a pellet having a size in the range of 0,1 to 4,0 mm, such as in the range 0,5 to 3 mm, in the range 1,0 to 2,5 mm and in the range 1,5 to 2,1 mm. A range from 1,7 to 2,0 mm is preferred.

The size of the pellet can vary depending of the release rate desired. it is presently preferred that 30-50%, preferably 35-45% of said tetracycline compound is released from said pellets in 20 minutes when suspended in water having a pH of 7,2 at ambient temperature (37 C) at a drug concentration of about 100 mg of drug/900 ml of water, and that 60- 85%, preferably 65-80% of said tetracycline compound is released from said pellets in 60 minutes when suspended in water having a pH of 7,2 at ambient temperature (37 C) at a drug concentration of about 100 mg of drug/900 ml of water.

The invention also relates to a capsule, such as a hard gelatine capsule, which contains a plurality of the pellets as defined above, especially a controlled release * S * * , S..

* .) . S. * * * * S S * * * ** * * S * * S S 5 * S S 5 * S S S * 0*S *i* ,.. * * pharmaceutical composition in oral dosage unit form comprising a gelatine capsule filled solely with pellets having an average diameter of from about 0.1 to about 3.5 millimeters, each pellet being similar in composition and comprising an effective antibacterial amount of a 7-or 9or a non-toxic acid addition salt thereof, a pharmaceutically acceptable excipjent as defined above, and a polymer, such as a polymer defined above.

A presently preferred embodiment is a capsule filled with a number of spherical pellets comprising minocycline, glycerol monostearate polyvinyl pyrrolidone (such as povidone) and microcrystalline cellulose, the pellets having an average size from 1,0 to 2,5 mm.

A capsule of the invention may have the following dissolution profile in water, 37 C: In 20 minutes: Between 24 and 35%, such as 27-32%, is dissolved In 50 minutes: Between 47 and 62%, such as 51-57%, is dissolved In 180 minutes: More than 80% is dissolved An other embodiment relates to a capsule which comprises pellets comprising a tetracycline compound or a non-toxic acid addition salt thereof and at least one Pharmaceutically acceptable excipient selected from the group consisting of waxes; fats; esters of fatty acids with polyols; monoglycerides; diglycericies; triglycerides; and mixtures thereof, said capsule when containing 100 mg of minocycline (base equivalent) has the following pharmacokinetic data in fasted state: AUC (ng.h/ml) in the range of 10000-35000, preferably in the range 15000-27000, and more preferably in the range 18000-25000, and most preferably in the range 19000- 23000. Cmax (ng/ml) should be in the range 700-2800, * * p * **S * S * * ** * S S S * S p * S I 55 * S * p * * * S * a * * I S * * * *5* (IS IS. * * preferably in the range 1000-2000, more preferably in the range 1200-1800, and presently most preferred in the range 1400-1600. Tmax (h) shound be in the range 1,0 to 2,0, more preferably in the range 1,2 to 1,8, and most preferably in the range 1,4 to 1,6.

The invention also relates to a pharmaceutical composition, e.g. capsule or dosage form as defined above, which reaches a peak concentration (Cmax) in serum of the tetracycline released in no more than 4 hours, such as from 1 to2 hours or from 1,25 to 1,75 hours, after administration in fasted state. Preferably, minocycline is administered, eg. as the hydrochloride.

The Cmax is calculated when a 100 mg single dose, calculated as minocycline base is administered.

The invention further relates to a pharmaceuic composition, e.g. capsule or dosage form as defined above, which has a Cmax in the range 1000-2000 ng/ml (such as in the range 1300-1700 or 1400-1600) and/or an AUC (extrapolated to infinity) in the range 15000-27000 ng x h/mi (such as in the range 19000-24000 or 20000- 23000) when 100 mg of the tetracycline (equivalent to the base) is administered in fasted state. Preferably, the tetracycline is minocycline, and presently most preferred minocycline hydrochloride.

A further embodiment relates to a method for producing the composition and pellets of the invention, said method comprising a combination of the following steps: - The tetracycline drug is mixed with the excipient as defined above (eg. glycerol monostearate), preferably whilst being heated in order to facilitate mixing, eg. to more than 50, more than 55, or more than 60 C.

* I * * * III * * I I a. * * * * * * * * * . a S* * S S S * * * a * a * * I I S * II. gas a., * * - The temperature may be allowed to drop, eg to below or below 40 C, preferably under mixing.

- The optionally cooled granulate, preferably milled, is blended with one or more polymers. If polyvinyl pyrrolidone is added, a Solution (eg. dissolved in IMS/water, such as in a 50-60 v/v solution) is preferably used.

- If needed, an additional volume of IMS/water is added until the granule is sufficiently wet for extrusion. The wet granule is extruded using an extruder fitted with a suitable screen, and spheronized using a spheroniser at sufficient speed, The process is continued until the extrudate has rounded to form spheroids of the desired size. The pellets are dried, screened and blended with purified talc.

It has been surprisingly found that when a combination of water and IMS is used as the granulating agent, the process for the manufacture of the pharmaceutical composition proceeds without degradation of the tetracycline and without poor extrusion. When water alone is used as the granulating agent, the active degrades. When IMS is used alone as the granulating agent, it evaporates rapidly and extrusion is poor.

DEFINITIONS

The term "Tetracycline" should be understood broadly and relates to tetracycline compounds in general. The term comprises members of the tetracycline family comprising substituted 7- and/or 9-amino tetracyclines. Typical compounds are, for example, * * I * * * * I * * * * * I * S S S S * 5 * S * * I S a * * ** * I S * * S S S * * S.. *., I S 7isopropylamino... 6 -deoxy- G-demethyltetracyci me, 9 -methylamino... 6 -deoxy- G-demethyltetracyj 9- isopropylammno... 6 -deoxyG-demethyltetracycijne 7i9-di(ethylamjno) 9-dimethylamjno 6 -deoxyG-demethyltetracycjj 7-rnethylamino.. G-deoxytetracyii 7, 9-di 7-diethylamino G-deoxytetracylj 9 -diethylamino G-tleoxytetracyljne 7, 9-cU (methylethylamiflo) -G-deoxytetracycjn, 7methy1amino...9...ethy1ajfl06 and 9.

Preferred members of this family comprise tetracycline compounds Selected from * (a) * (b) 7methylamino6...deo.6djmethyltt * (c) 9methylamino_6..deoxy_6demethyltti * (d) * (e) 7-isopropylamjflo.....06 demethyl - tetracycline; * (f) a non-toxic acid addition salt of (a) (e), inclusive or * (g) a mixture of any of the foregoing.

An interesting tetracycline compound is 7-dimethylamino (minocyclmne) and its non- toxic acid addition salts, e.g., hydrochloric sulfonic, trichioroacetic acid salts, and the like, especially preferably the hydrochloric acid addition salts.

The tetracycline compounds and methods for their preparation are disclosed in the prior art and are know to the skilled artisan. For best results, the controlled release composition of this invention in dosage unit form * S * * * *S* S S 5 a ** * * S * * * S * * * S * l* * I * * * S * 5 * S * * * S S * * * *5. **, *** . a may, for example, Contain from 25 to 200 mg, and more Preferably 50 and ioo mg, of the tetracycline Compound, f or example, minocycline hydrochloride.

The term "pellet" comprises rounded; oblong; spherical; ellipsoid; beadshaped; rod-shaped and cylindrical particles having for example an average size of o,i to 4,0 mm. The pellet can be obtained by granulatj spheronjsaj0 by spraying a core seed with the core element formulation in a flujdjzed bed coater, using a centrifugal granulao or spheronjzer by applying tetracycline and excipient onto Spheres (such as sugar spheres, European Pharmacopoeia 4th edition p 1973), etc. The term "spheres" in relation to the pellet is well known in the pharmaceutjc art, and means spherical granules having a average diameter of approximately 0.1 to 3.5 millimeters, preferably from 0.5 to 2,5 mm. The spheres can have a average diameter of at least 0,5: 0, 8; 1,0; 1,3; 1,5; or even at least 1,7 mm, and an average diameter of at most 3,0 mm, 2,8; 2,6, 2,4; 2,2; 2,0; 1,7; or even at most i,s mm. Ranges can be produced by freely combining a lower average diameter with an upper average diameter, eg. pellets having an average diameter falling within the range 1,7 to 2,0 mm is an embodiment of the present invention.

The term "wax" comprises natural and artificial waxes.

The term "fat" comprises natural and artificial fats.

The term "polyol" comprises molecules having a carbon backbone and at least two hydroxy groups, such as propylenglycol, ethylenglycoi butanetrjoi, butanedjol (including 2,3- or 1,2- butylenglycoi and 1,4butandiol) ]-,3-propandiol glycerol and derivatives thereof.

* * S 5 * *..

* S * S 5. * * S * S S * . S S * S S I. * * * . S S I * * . . 5 0 S S S S **S *IS 55S S It is also among the features of the invention to provide oral dosage units by forming the pellets to tablets.

In some features of the invention, especially when the drug is coated on the pellet, the pellets can include a layer of a polymer substantially uniformly coating each of said pellets, such as a polymer being slowly erodable in the human stomach and rapidly erodable in the human small intestine upon oral administration.

In both instances.(ie coated or uncoated pellets), a water-soluble tetracycline compound, i.e., one which requires less than 500 parts by volume of water to dissolve i part by weight of the tetracycline compound at ambient temperature is preferred. Moreover, using either uncoated pellets or coated pellets, it is presently pref erred that 65-8O of the tetracycline compound will be released from spherical pellets within one hour, and that it will be substantially completely released, i.e., more than 85 percent released, in no more than about 120 minutes when suspended in deionized water (pH about 7,2) at body temperatures e.g., 37 C, at a drug concentration of about 100 mg/900 ml w/v. In the film coated version, ultra thin coatings are preferred for this reason.

Ultrathin means, for purposes of this disclosure, that the weight of the film will be from 2 to less than about 10, preferably from about 2 to about 5 percent by weight based on the weight of the film coated pellets.

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 either be somewhat erodable in gastric juice and/or used in ultrathin layer or layers to permit release of a minor proportion of the tetracycline compound in the stomach, the importance of which has been set forth above.

* * * . S ** * S * * ** * p a * a * a a a * * * ** * S S S S S 5 * . I * * a a - S * a.. *.. *** S * Although from 2 to less than about 10 weight percent of film content based on the weight of the film coated spheres is suitable for most readily gastric juice erodable polymers, it is preferred to use 2 to 5 percent of any film because thin layers of all polymers, even those of somewhat higher resistances to acidic gastric juices, will permit release of the required small amounts of tetracycline compound in the stomach.

Illustrative but not limiting film forming polymers are cellulose and acrylic acid based polymers. Particularly to be mentioned are methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyi methyl cellulose, hydroxypropyi methyl cellulose phthalate, cellulose acetate phthalate, hydroxypropyi methylcellulose succinate, polymers and copolymers of (meth)acryljc acid and (meth) acryljc acid methyl ester and mixtures of any of the foregoing. The coatings can include conventional additives, such as plasticizers, pigments, colorants, etc. The plasticizers can include mineral oil, high boiling esters, vegetable oils and the like. Commercial coating compositions found to be useful include Eudragit a product of Rohm Pharma, Weiterstadt, Germany and Surelease , a product of Colorcon, Inc., West Point, PA. The former comprises an anionic polymerizate of methacrylic acid and methyl methacrylate The latter comprises an aqueous dispersion of ethyl cellulose, dibutyl sebacate, oleic acid, fumed silica, and ammonium hydroxide.

Preferred as coating materials are ethyl-cellulose and hydroxypropyi methylcellulose, and the commercial coatings exemplified herein.

A suitable form of ethylcellulos is one having a viscosity in the range of 5 to 100 cps at 20 C (U.s.

National Formulary XIII) (content of ethoxy groups 44 to 51& by weight), and more particularly a viscosity of 50 * S * * S *Si S * * * ** S I * S I * I * * S S * *s * S I 5 * I S * * I S * , S a * a * *IS gel *5. S 5 cps at 20 C (content of ethoxy groups 48 to 49 by weight). A suitable form of hydroxypropyi methy1celluos is one having a Viscosity in the range 3 to 100 cps at 20 C. (U.S. National Formulary XIII), and more particularly a viscosity of 6 cps at 20 C.

The spheres containing tetracycline compound thereon or therein can, if desired, be coated with an aqueous or organic solvent solution of the desired film forming polymer, using fluid bed technology or pan-coating, and the like, but preferably fluid beds are used.

It is preferred hbwever if the pellets of the invention are uncoated.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is a graphical representation of the release of minocycline hydrochloride from uncoated spheres in accordance with this invention in acid, pH 1,2, with EP paddle apparatus at 50 rpm. The graphically represented data appears below the figure.

Fig. 2 is a graphical representation of the release of minocycline hydrochloride from uncoated spheres in accordance with this invention in deionized water, pH 7,2 with EP paddle apparatus at 50 rpm. The graphically represented data appears below the figure.

Fig. 3 is a graphical representation of the release of minocycline hydrochloride from encapsulated uncoated spheres in accordance with this invention in various media. The underlying data is found in example 6.

* * , I * *.* * 0 * 0 ** , * S I I * I * a * I I.1 * I I I I I * * I I I I I 0 0 * SI. **0 Itt I *

EXAMPLE 1

Determination of the Dissolution of tetracycline capsules, exemplified by Minocycline MR Capsules, by UV Reagents Minocycline Hydrochloride Characterised reference standard Water RO, deionised or distilled Dissolution Medium Water Dissolution Conditions Manual and Automated Apparatus: EP paddle apparatus (paddles/round bottom vessels) Paddle speed: 50rpm Cell pathlength: 0.5cm Wavelength: 348nm Run time: 3 hours Sampling volume: lOmi Filters: 20/.i polyethylene Automated Pump setting 3.9ml/min Standard Preparation 1. Transfer approximately 60mg of Minocycline Hydrochloride characterised reference standard, accurately weighed, to a lOOml volumetric flask.

2. Dissolve in and dilute to volume with dissolution medium (Solution A).

3. Dilute lOmi of Solution A to 50m1 with dissolution medium. Mix well.

I * * . I,.

* * I * ** * * S S S * S S a * * , ** S * * 5 S I I * * I * * * S S * * I 555 5a* *** * S igcgdure (Manual and AutomatgJ 1. Transfer one capsule held in a three pronged capsule weight (sinker) into each of 6 dissolution vessels containing 900m1 of degassed dissolution medium at 37 C 0.5 C and proceed according to the stated Conditions.

2. Measure the absorbance of the standard solution using dissolution medium as the reference solvent.

3. Measure the absorbance of the sample Solution at 5 minute intervals between initial and 1 hour and at minute intervals between i and 3 hours using dissolution thedium as the reference solvent.

Calculation 1) Manual Minocycline dissolved = Wstd x P x Aspi x9 Astd x 1. 08 x 5 ii) Icalis dissolution software Input standard concentration with respect to minocycline: Minocycline concentration (mg/L) = Wstd x 2 1.08 Where: Aspi = sample absorbance Wstd = Minocycj.jne HC1 standard weight (mg) Astd = standard absorbance P = potency of reference standard, expressed as a decimal

EXAMPLE 2

Manufacturing of pellets comprising minocycljne, povidone, glycerol monostearate and talc.

Minocycljne hydrochloride: 60088 g; Glycerol monostearate 40-55: 10360 g; * p p p * ** * . I * ii * * S I S * . I * * S I.5 S * * * * * S p 5 * I S * as. a.. *.* * S Microcrystalline cellulose 101: 23828 g; Povidone K-30: 4662 g; Purified talc: 518 g; Purified water; Industrial methylated spirit 74 OP (IMS) 1. The minocycline HC1 is placed into a suitable mixer.

The glycerol monostearate is screened through an appropriate mesh and added to the mixer.

2. The powder bed is heated whilst mixing.

3. When the powder bed temperature has reached 65 degrees C the powder bed is cooled whilst mixing.

4. Mixing is stopped when the bed temperature has dropped to below 40 degrees C. 5. The cooled granulate is milled.

6. The milled granule is placed in a suitable mixer and blended with microcrystalline cellulose.

7. A Solution of povidone dissolved in IMS/water 56 v/v is prepared.

8. The povidone solution is used to granule the blend from step 6 with an additional volume of IMS/water being added until the granule is sufficiently wet for extrusion.

9. A sample of the wet granule is extruded using an extruder fitted with a suitable screen.

10. Spheronizing the sample using a spheroniser at sufficient speed, The process is continued until the extrudate has rounded to form spheroids of the desired size.

11. The pellets are dried.

12. The dried pellets are screened.

13. The pellet fraction and the purified talc are placed in a suitbale mixer and blended.

14. The pellets are encapsulated.

* * * , . ft.

* . V I it * * . I I * I * S S * I ** * I I I I * * * * I t * * S * SI. SI. .55 I *

EXAMPLE 3

Composition of a capsule of the invention Pellet: Minocycline hydrochloride 116mg; Glycerol monostearate 20mg; Microcrystalline cellulose 46mg; Povidone K-30 9mg; Purified water ND; Industrial methylated spirit 74 OP BP ND.

Hard gelatin capsule: Gelatin 80-84%- Water 14.5%- Colours up to 100%-

EXAMPLE 4

The dioluti0 rate of the capsules made according to example 2 is measured according to the procedure in

example i.

The dissolution in water at neutral pH (7,2) and at a temperature of 37 degrees C is found as follows: In 20 minutes: Between 24 and 35%- is dissolved In 50 minutes: Between 47 and 62%- is dissolved In 180 minutes: More than 80%- is dissolved

EXAMPLE 5

Single dosis experiment.

Pharmacokjnetic Variables For Minocycline Modifed Release Capsules in the fasted state.

* . . * * *5* * S * * ** * S a I a * . S S S S * ** * . I S I S I S * * S I 5 * * S * .5* III **I * S Minocycline was assayed using a validated high performance liquid chromatographic method and the analytical work performed in accordance with good laboratory practice guidelines. The following pharmacokjnetic variables were measured: maximum concentration (Cmax), time to maximum concentration (Tmax), area under the curve to the last data point and extrapolated to infinity (AUCO-t and AUC0-)' apparent terminal half-life (tl/2), ratio of Cmax and AUC0-. All analyses were performed using BIOPRO (v3.2). The results are shown below: ______________ Minocycline Variable Unit Mean C ng/ml 1492 T h 1.5 AUCO ng.h/ml 20288 AUCOOO ng.h/ml 21798 h 13.8 SX/AUCOIO 1/h 0.07 Pharmacokjnetjc Variables for Minocycline Modified Release Capsules in the fed state Minocycline Variable - Unit Mean - ng/ml 1266 AUCO - ng.h/ml 20531 AUC0ID - ng.h/ml 22399 T1/2 14.5 Cmax/AUCo 1/h 0.06 I * S * * S *!* * S * S as t S I S * I S I * * * ** * S * a * * a * * * S 5 5 I I S * a.. a.. us S * In the experiments, a capsule of the invention (example 3) was used, comprising Minocycljne hydrochloride in an amount equivalent to 100 mg Minocycline base EXA}IP 6 Dissolution in various media Batch CO563 is Minocycline hydrochloride MR capsules.

Method details - Paddles, round bottom vessels, 50rpm, 900m1, 348nm.

DiSsolutIon Time CT0563 0.1M CT0563 CT0563 CT0563 CT0563 (mins) HC1 pH3 pH5 pH8 water 0 0 0 0 0 0 4 1 1 2 2 31 12 13 12 12 47 20 22 20 19 57 27 28 27 26 64 32 34 32 31 69 37 39 36 35 73 41 43 40 39 77 44 47 44 43 79 47 50 47 46 82 50 53 50 48 83 53 56 52 51 84 55 58 55 53 87 61 64 61 59 87 66 69 66 64 87 70 73 70 68 88 74 77 74 72 88 76 79 77 75 88 79 81 80 77 88 81 8382 79 88 82 85 84 81 * * * , I *I* * S * I ** * * I * * * I S I S S * I. * S S * * . I * * I * I * * * * S * *I* 115 uS S 5 In the experiments, a capsule of the invention was used, comprising Minocycline hydrochloride in an amount equivalent to 100 mg Minocycline base.

Remarks: The above-mentioned patents and publications are incorporated herein by reference.

Many variations will suggest themselves to those skilled in this art in light of the foregoing detailed description. For example, instead of 7dimethyl-6-deoxy...

G-demethyltetracycijne hydrochloride, the free base, the sulfuric acid and the trichioroacetic acid addition salts can be used. Instead of 7dimethyl--6-deoxy..6...

demethyltetracycline hydrochloride, the hydrochiorides of the following compounds can be used: 7-methylamino-6- deoxy-6-demethyltetracycline; 9-methy1-amino6deoxy..6...

demethyltetracyciine; 7-ethylamino-6-deoxyG...

demethyltetracycline; and 7-isopropy1amino6deoxy...6....

demethyltetracycline. As a film former, ethyl cellulose can be used alone. The pellets can be filled into either hard gelatin or soft gelatin capsules in conventional capsule-filling machines, to provide 50 and 100 milligrams of minocycline hydrochloride content in each capsule. The pellets can also be mixed with conventional pharmaceutical binders and/or excipients and compressed into tablets. All such obvious variations are within the full-intended scope of the appended claims.

Claims

* I * I * is. * . 4 * I. I 4 4 4 * I * S * I Is * S * * . . S * S * I * I 4 * I.. e.. a.. * * CLAIMS

1. A pharmaceutical composition which comprises (I) a tetracycline compound or a non-toxic acid addition salt thereof; (II) at least one pharmaceutically acceptable excipient selected from the group Consisting of waxes; fats; esters of fatty acids with polyols; monoglycerides; diglycerides; and,triglycerjdes said excipient (or excipients) beingpresent in an amount of 8-35 of the amount of the tetracycline (w/w); and (III) at least one polymer selected from the group consisting of: microcrystalline cellulose; polyvinylpyrrol idone; hydroxypropylmethyl cellulose; methylcellulose; ethylcellulose; hydroxyethyl cellulose; hydroxypropyl cellulose; hydroxypropyl methylcellulose phthalate; cellulose acetate phthalate; hydroxypropy].

methylcellulose succinate; a polymer or copolymer of (meth)acrylic acid or an ester thereof; and sodium carboxymethyj. ce1lulose said polymer (or polymers) being present in an amount of 2O-l00 of the amount of the tetracycline (w/w)

2. A pharmaceutical composition according to claim 1 in which said excipient is a mono, di or tn-ester of glycerol with a saturated fatty acid having more than 10 carbon atoms.

3. A pharmaceutical composition according to claim 2 wherein said excipient is glycerol monostearate.

4. A pharmaceutical composition according to claim 3 comprising 16 to 2O% glycerol monostearate relative to the amount of the tetracycline (w/w) * . Is.

* S I * ** , . , * S S I a S * ** * . S *

5 5 I * * . S * * a. . * S ISa I.. I* a * 5. A pharmaceutical composition according to any one of claims 1 to 4 wherein said polymer is microcrystalline cellulose.

6. A pharmaceutical composition according to claim 5 comprising 35 to 45 microcrystalline cellulose relative to the amount of the tetracycline (w/w).

7. A pharmaceutical composition as claimed in claim 1 to 6 further comprising polyvinyl pyrrolidone.

8. A pharmaceutical composition according to claim 7 comprising 6 to 9 polyvinyl pyrrolidone relative to the amount of the tetracycline (w/w).

9. A pharmaceutical composition as claimed in any one of claims 1 to 8 wherein the tetracycline compound or salt thereof is minocycline or a salt thereof.

10. A pharmaceutical composition as claimed in claim 9 wherein the tetracycline compound or salt thereof is minocyc].jne hydrochloride.

11. A pharmaceutical composition as claimed in claim 10 which comprises minocycline hydrochloride and, measured relative to the weight of minocycline 1-Id (w/w), 10-30% glycerol monostearate, 20-60% microcrystalline cellulose and 3-15% polyvinyl pyrrolidone.

12. A pharmaceutical composition according to any of the preceding claims, wherein said composition is formulated as a plurality of pellets having a size in the range of 0.1 to 4.0 mm.

13. A pharmaceutical composition according to any of the preceding claims, wherein said composition is formulated I w * . I III * I I * II I V I I 4 4 I 4 4 4 4 I 44 * I I $ I I I I I 4 * I ISP lIP III - as a plurality of pellets having a size in the range 0.5 to 2 mm.

14. A pharmaceutjcai composition according to claim 12 or 13 wherein 3050%- of said tetracycline compound is released from said pellets in 20 minutes when suspended in water having a pH of 7,2 at ambient temperature (37 C) at a drug concentration of about ioo mg of drug/900 ml of water.

15. A pharmaceuticai composition according to claim 14 wherein 35-45% of said tetracycline compound is released from said pellets in 20 minutes when suspended in water having a pH of 7,2 at ambient temperature (37 C) at a drug concentration of about ioo mg of drug/900 ml of water.

16. A pharmaceutical composition according to claim 12 or 13 wherein 60-85%- of said tetracycline compound is released from said pellets in 60 minutes when suspended in water having a pH of 7,2 at ambient temperature (37 C) at a drug concentration of about ioo mg of drug/900 ml of water.

17. A pharmaceutjcai composition according to claim 16 - wherein 65-80%of said tetracycline compound is released from said pellets in 60 minutes when suspended in water having a pH of 7,2 at ambient temperature (37 C) at a drug concentration of about ioo mg of drug/900 ml of water.

18. A pharmaceutical composition comprising 55-65%- wt minocycline hydrochloride, 9-12 %wt glycerol monostearate, 22-27 %wt microcrystalline cellulose, and 3-6 %wt povidone.

I I * i I)1t * * * i* , I I - * I I I $ S V It * V I $ * VI 24 III:.. *.

19. A pharmaceutical composition as claimed in claim 1 to 18 formulated as a capsule which contains a plurality of pellets.

20. A composition as claimed in claim 19 wherein said capsule is a hard gelatine capsule.

21. A pharmaceuticai composition as claimed in any one of claims i to 20 being a controlled release pharmaceutical composition in oral dosage unit form.

22. A pharmaceuticai composition according to any of the preceding claims, which reaches a peak concentration (Cmax) in serum of the tetracycline released in no more than 4 hours after administration in fasted state.

23. A pharmaceutjcai composition according to any of the preceding claims, which reaches a peak concentration (Cmax) in serum of the tetracycline released in 1-2 hours after administration in fasted state.

24. A pharmaceutical composition or capsule according to any of the preceding claims, which has a Cmax in the range 1000-2000 ng/ml and/or an AUC (extrapolated to infinity) in the range 15000-27000 ng x h/ml when 100 mg of the tetracycline is administered in fasted state.

25. A pharmaceutjcai composition as claimed in any preceding claim additionally comprising talc.

26. A process for the preparation of a pharmaceutical composition comprising (i) mixing a tetracycline or non-toxic additional salt thereof with an excipient selected from the group consisting of waxes; fats; esters of fatty acids with * . S * S V. . S S q5 * * S S S * S S 5 * S S a* S S * * 5 5 * S *s *l 556 * * S S * * S 5 * polyols; monoglycerides; diglycerjdes; triglycerides said excipient (or excipients) being present in an amount of 8-35% of the amount of the tetracycline (w/w); (ii) blending with at least one polymer selected from the group consisting Of: microcrystalline cellulose; Polyviny].pyrrolidone; hydroxypropylmethyl cellulose; methylcellulose; ethylcellulose; hydroxyethyl cellulose; hydroxypropyl cellulose; hydroxypropyl methylcel1u1o5 phthalate; cellulose acetate phthalate; hydroxypropyi methylcellulose succinate; a polymer or copolymer of (meth) acrylic acid or an ester thereof; sodium carboxymethylcellulose said polymer (or polymers) being present in an amount of 2O-1OO6 of the amount of the tetracycline (w/w); (iii) adding a solution of polyvinyl pyrrolidone dissolved in Industrial Methylated Spirit/water (iv) granulating and then extruding the resulting mixture.

27. A process as claimed in claim 26 wherein an IMS/water solution of 5O6O V/v is used.

28. A pharmaceutical composition substantially as hereinbefore described with reference to any of the

Examples.