.
`Umted States Patent
`
`[19]
`
`USOOS348748A
`[11] Patent Number:
`
`5,348,748
`
`Sheth et a1.
`
`[45] Date of Patent:
`
`Sep. 20, 1994
`
`[75]
`
`[54] PULSATILE ONCE-A-DAY DELIVERY
`SYSTEMS FOR MINOCYCLINE
`_
`‘
`.
`Inventors: Nitm V. Sheth, Middletown; Joseph
`J. Valorose, Jr., Montgomery, both
`of N.Y.; Keith A. Ellway, Shir-fell
`Heath, United Kingdom;
`MaduraiGurusamy Ganesan, Suffern,
`N.Y.; Kieran G. Mooney, Whitstable,
`United Kingdom; Jerry B, JOhnson,
`Upper Saddle River, NJ.
`
`[73] Assignee: American Cyanamid Company,
`Wayne, NJ.
`
`.
`[21] Appl. No.. 81’6”
`[22] Filed:
`Jun. 23, 1993
`
`Related US. Application Data
`
`[62]
`
`Division of Ser. No. 844,109, Mar. 2, 1992, Pat. No.
`5,262,173.
`
`[51]
`
`Int. Cl.5 ......................... A61K 9/54; A61K 9/56;
`A61K 9/53
`[52] U.S. Cl. .................................... 424/494; 424/458;
`424/461? 424/462; 424/490; 424/493; 424/495;
`424M973 424/498
`[58] Field of Search ............... 424/458, 461, 462, 490,
`424/493’ 494’ 495’ 497’ 498
`References Cited
`US PATENT DOCUMENTS
`
`[56]
`
`
`3,080,294 3/1963 Shepard ..
`------ 167/32
`3,865,935
`2/1975 Amannw
`
`424/181
`...........
`4,138,475
`2/1979 McAnishe a1.
`
`""" 13:23
`........
`4,173,626 11/1979 Dempski et a1.
`
`...... 424/81
`..
`4,250,166 2/1981 Maekawa et a1.
`
`4,353,887 10/1982 Hess et al. ..................... 424/15
`4,606,909
`8/1986 Bechgaard et a1. ................... 424/21
`
`4,784,858 11/1988 Ventouras ........................... 424/468
`
`2/1989 Joshi et a1. .................. 424/458
`4,808,413
`6/1989 Valorose, Jr. et a1.
`...... 424/468
`4,837,030
`
`5,133,974 7/1992 Paradissis et a1. .......... 424/480
`
`1/1994 Carli et a1. ............... 424/469
`5,275,824
`
`
`2/1994 Doyon et al. ............... 424/468
`5,283,065
`5,286,497 2/1994 Hendrickson et a1.
`............. 424/490
`OTHER PUBLICATIONS
`
`Abstract Japan Appln. No. 51-139712 and Japanese
`text.
`Abstract Japan Appln. No. 62-226926 and Japanese
`text
`
`Primary Examiner—Thurman K. Page
`Assistant Examiner—James M. Spear
`Attorney, Agent, or Firm—James Costigan
`
`[57]
`
`ABSTRACI‘
`
`Pharmaceutical delivery systems containing 7-dimeth-
`yl-6-deoxy-6-demethyltetracycline or a non-toxic acid
`.
`.
`.
`.
`.
`.
`additlon salt thereof comprlsmg mlxtures of a minor
`proportion of slow-release blended polymer coated
`spherical granules adapted to release part of the mino-
`cycline in a medium having a pH Of below 39 and the
`rest in the range of from about 4.0 to about 7.5 and a
`major proportion of coated or uncoated quick-release
`granules adapted to release minocycline in a medium
`having a pH of less than about 3.9 and oral dosage unit
`form capsules containing the above are provided. These
`systems and formulations provide enhanced therapeutic
`blood levels of minocycline for at least about 24 hours
`when administered to a subject only once-a-day, regard-
`less of whether the patient is fed or fasted. Methods for
`the preparation of the systems and formulations are
`.
`PIOVIded as we“-
`
`24 Claims, 3 Drawing Sheets
`
`PREPARATION OF SPHERICAL GRAUNULES
`
`DRUG
`EXCIR/EN 77$)
`
`GRANULA TOR
`
`GRA NULA TING
`LIQUID
`
`EX TRUDER
`
`0.7-2.5 MM
`PLA TE
`
`~
`
`0R TRA Y DRYER
`
`SPHERON/ZER
`
`FLUID BED DRYER
`
`DRIED SPHER/CAL GRANULES
`
`1
`
`

`

`US. Patent
`
`Sep. 20, 1994
`
`Sheet 1 of 3
`
`5,348,748
`
`FIG.
`
`I
`
`PREPARATION OF SPHERICAL GRAUNULES
`
`DRUG
`
`EXC/PIEN TIS)
`
`OR TRAY DRYER
`
`GRA NULA TOR
`
`GRA NULA TING
`LIQUID
`
`EX TRUDER
`
`0.7-2.5 MM
`PLA TE
`
`SPHERON/ZER
`
`FLUID BED DRYER
`
`DRIED SPHER/CAL GRANULES
`
`FIG. 2
`
`PREPARA T/ON 0F COA TED SPHER/CAL GRANULES
`
`DRIED SPHER/CAL GRANULES (FROM A)
`
`COA TING
`
`POL YMER
`
`
`
`
`
`
`COA TED OUICK
`RELEASE SPHER/CAL
`
`COA TED DELA YED
`
`SPHERICAL GRANULES
`
`
`GRANULES
`
`
`2
`
`

`

`US. Patent
`
`Sep. 20, 1994
`
`Sheet 2 of 3
`
`5,348,748
`
`.
`F/G_ 3
`
`—+— COMPARA T/VE EXAMPLE 15*
`—A— COMPAPA T/VE EXAMPLE zc *
`—-o- EXAMPLE /
`
`
`
`
`
`ZM/NOCYCL/NED/SSOLVED
`
`MINOCYCL/NE DISSOLUTION PROFILES
`[0000M Y. 321 CAPSULES IN pH 4.0 MED/UM
`
`
`
`o
`
`30
`
`so
`TIME (M/NS)
`
`90
`
`I20
`
`FIG. 4
`
`—+— COMPAPA T/VE EXAMPLE 15*
`——A— COMPAPA T/VE EXAMPLE 16*
`—o— EXAMPLE /
`MINOCYCL/NE DISSOLUTION PROF/LES
`2000137. JZ IZZ' CAPSULES /N pH 6.0 MED/UM
`
`I
`
`100
`
`80
`
`60
`
`
`
`zM/NOCYCL/NED/SSOLVED
`
`
`
`40
`
`20
`
`60
`TIME (M/NS)
`
`90
`
`720
`
`3
`
`

`

`US. Patent
`
`Sep. 20, 1994
`
`Sheet 3 of 3
`
`5,348,748
`
`N.xm4*,2.xm$80*@.xm$8+*S.xm$8a
`
`VN
`
`ON9Qmv
`
`«MQDOTCWEE
`
`
`
`«Q.«5.0200¥D~Em25$NZZUXQOZS
`
`
`
`RE.0359MBZMQMKMQgE..qNEHQQ
`
`MSt
`
`MEAN MINOCYCL/NE SERUM CONC.
`
`(MCG/ML)
`
`4
`
`
`

`

`1
`
`5,348,748
`
`PULSATILE ONCE-A-DAY DELIVERY SYSTEMS
`FOR MINOCYCLINE
`
`This is a divisional application, of application Ser. No,
`07/844,109, filed Mar. 2, 1992, now U.S. Pat. No.
`5,262,173.
`FIELD OF THE INVENTION
`
`The invention relates to pharmaceutical delivery
`systems for the prolonged controlled release of 7-dime-
`thylamino-6-deoxy-6-demethyltetracycline
`(minocy-
`cline) or non-toxic acid addition salts thereof. It pro-
`vides a once-a—day delivery system which maintains
`therapeutic blood level concentrations of the medica-
`ment in a patient for twenty-four hours by the once-a-
`day administration of improved custom designed for-
`mulations comprising a major proportion of an initial
`loading or first pulse of minocycline containing quick
`release granules and a minor proportion of a secondary
`loading or second pulse of minocycline containing
`blended pH—sensitive
`and pH-indifferent polymer
`coated spherical granules administered simultaneously.
`Spheronized pharmaceutical compositions comprising a
`major proportion of quick-release initial and a minor
`proportion of slow-release secondary minocycline load-
`ings as well as oral dosage unit forms of all of the above
`are provided as well.
`These pharmaceutical delivery systems, compositions
`and oral dosage unit forms, in comparison with those
`containing only a minor proportion of the initial quick-
`release loading of available minocycline, will provide
`more than 10% higher plasma level concentrations of
`minocycline in the therapeutic range for effective anti-
`bacterial activity for up to about twenty-four hours and
`they have the same excellent absorption characteristics
`regardless of whether they are administered to fed or
`fasting patients.
`BACKGROUND OF THE INVENTION
`
`compound, 7-dimethylamino-6-
`The tetracycline
`deoxy-6-demethyltetracycline, and its non-toxic acid
`addition salts are widely used in therapy primarily for
`their antimicrobial effects. Commonly assigned Boothe
`et al, U.S. Pat. No. 3,148,212, and Pesti et al, US. Pat.
`No. 3,226,436, describe the preparation of minocycline.
`Although the compounds have achieved widespread
`use in oral dosage forms, they have several drawbacks.
`The minimum therapeutically effective blood serum
`or plasma concentration level of minocycline in a
`human subject varies according to the organism causing
`the infection. The concentration is determined in vivo
`by clinical evaluation and in vitro by microbiological
`assays. Currently, the minimum therapeutically effec-
`tive concentration is believed to be in the range of from
`about 0.1 to about 1.0 mcg of minocycline/m1 of serum.
`Organisms currently known to be susceptible to
`minocycline therapy include a wide range of gram-neg-
`ative and gram-positive bacteria including, but not lim-
`ited to agents of rickettsiae (Rocky Mountain spotted
`fever, typhus fever and the typhus group, Q fever, ric-
`kettsial pox,
`tick fevers); Mycoplasma pneumonias
`(PPLO, Eaton agent); agents of psittacosis and ornitho-
`sis; agents of lymphogranuloma venereum and granu-
`loma inguinale; the spirochetal agent of relapsing fever
`(BorreIia recurrentis); the agent of Lyme disease (Bor—
`reIia burgdorfeni), the agents of acne (Propionibacterium
`Corynebacterium acnes); the microorganisms Haemoph-
`ilus ducreyi (chancroid), Yersinia pestis and Francisella
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`65
`
`2
`formerly Pasteurella pestis and Pasteurella
`tulorensis,
`tularensis, Bartonella bacilliformis, Bacteroides species,
`Vibrio cormmz and Vibrz'o fetus, Brucella species, Escher-
`ichia coli, Enterbacter aeragenes (formerly Aerobacter
`aerogenes), Shigella species, Mirna species, Herellea
`species, Haemophilus influenzas (respiratory infections),
`Klebsiella species (respiratory and urinary infections),
`many Streptococcus species including strains of Strepto-
`coccus pyogenes and Streptococcus faecalis, Streptococcus
`pneumonias, Staphylococcus aureus (skin and soft tissue
`infections), Neisserio gonorrhoeae, Neisseria meningitidis,
`Treponema pallidum and Treponema pertenue (syphilis
`and yaws), 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 discovery shows that minocycline is absorbed
`at different rates in different portions of the gastrointes—
`tinal tract. Intubation studies in human patients have
`demonstrated that bioavailability of minocycline in the
`gastrointestinal tract, based upon 100 percent absorp-
`tion in the stomach, is 106 percent in the duodenum, 80
`percent in the jejunum and 58 percent in the ileum,
`indicating that minocycline demonstrates reduced ab-
`sorption in the lower gastrointestinal tract.
`The human stomach empties in about one hour in a
`fasting subject and in about one to about four hours
`with food. The half life of minocycline when taken
`without food is approximately 10 hours. When taken
`with food, the half life is extended to approximately 14
`to 16 hours.
`
`It has not been possible to achieve a once-a-day thera-
`peutic blood level of minocycline using only delayed
`release granules of minocycline with or without food
`ingestion. Traditional pharmaceutical forms containing
`minocycline require frequent
`ingestion of multiple
`doses per day resulting in wide variations in serum
`concentration throughout the course of treatment and
`in poor patient compliance and traditional delayed re-
`lease forms containing minocycline are incompletely
`absorbed in the gastrointestinal tract. This indicates a
`need for a custom designed once-a-day delivery system
`for minocycline to provide optimal therapeutic effect
`and patient compliance.
`Lederle Laboratories has recently offered for use by
`the medical profession, capsules under the trademark
`MINOCIN® containing specially coated pellets of
`minocycline hydrochloride for oral administration. See,
`PDR 44th Ed. (Pages 1168—1170). In contrast to tablets
`and powder-filled capsules, pelletized minocycline hy-
`drochloride provides virtually complete absorption
`with dairy products and food. The capsules, however,
`are not intended to provide a once-a-day dosage form.
`Valorose et al, US. Pat. No. 4,837,030, disclose hard
`gelatin or soft gelatin capsules filled with minocycline
`comprising spherical granules. This patent teaches con-
`trolled release formulations of minocycline wherein the
`rate of release in the stomach and intestines is con-
`trolled. The delivery system may be comprised of
`coated or uncoated spheres. The medicament may be
`within the sphere or in the coating. Valorose further
`teaches coating the spherical granules with hydroxy-
`propyl methylcellulose and hydroxypropyl methylcel—
`lulose phthalate. The controlled release in Valorose,
`however, is not taught to be prolonged up to 24 hours.
`
`5
`
`

`

`5,348,748
`
`4
`minocycline in the stomach should reduce the long time
`effectiveness, but, as will be seen, single dose bioavaila-
`bility versus the reference tablet given twice a day is
`increased from 79% to 89%, and the latter is unaffected
`by food intake as is shown in the multidose studies.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`3
`Shepard, US. Pat. No. 3,080,294, discloses a sus-
`tained release pharmaceutical
`tablet comprising an
`inner core coated with multiple layers of an active med-
`icament mixture, each layer releasing a portion of active
`medicament as it is successively dissolved. Such layers
`are not pH adapted, however. Shepard further teaches
`sustained release pharmaceutical formulations wherein
`FIG. 1 is a graphic illustration of a method for the
`medicament coated pellets and uncoated medicament
`production of uncoated quick release granules and pre-
`pellets maintain therapeutic blood concentration levels
`cursors of blended polymer coated spherical granules
`for prolonged periods of time. The medicament may be
`according to the present invention.
`in the coating or in the core. Shepard also teaches the
`FIG. 2 is a graphic illustration of a method for the
`use of coatings comprised of cellulose esters and pH
`production of coated quick release granules and
`sensitive polymer coatings. As explained in example 4
`blended polymer coated spherical granules according
`of Shepard, the dosage forms are formulated so that a
`to the present invention.
`predetermined amount of active ingredient may be re-
`FIG. 3 is a graphic illustration of the release rate of
`leased in the stomach (pH less than 3.9) and a predeter—
`minocycline from blended polymer coated spherical
`mined amount may be released in the intestines (pH
`4—7.5) approximately.
`granules of this invention in comparison with those not
`of this invention in a medium having a pH of about 4.0.
`In copending, commonly assigned US. patent appli—
`cation, Ser. No. 07/410,708, filed Sep. 21, 1989, now
`FIG. 4 is a graphic illustration of the release rate of
`abandoned it is disclosed that a specific minocycline
`minocycline hydrochloride from blended polymer
`coated spherical granules as in FIG. 3 but in a medium
`composition can be formulated to provide at least mini-
`having a pH of 6.0.
`mum therapeutic serum levels of the minocycline in a
`FIG. 5 is a graphic illustration of blood serum con-
`human subject for about 24 hours through once-a—day
`centration levels of once-a—day administration of mino—
`two pulse administration systems, comprising an initial
`cycline to human subjects in an oral dosage unit forms
`loading component providing the first pulse which is
`according to the present invention, in two oral dosage
`absorbed up to 100 percent in the stomach and a second-
`unit forms not according to this invention and a twice-a—
`ary loading component providing the second pulse
`day administration of minocycline in oral dosage unit
`which is absorbed up to 100 percent in the duodenum
`and the upper part of the small intestine. Working exam— 30 form presently available from Lederle Laboratories.
`ples are provided which contain a minor proportion of
`SUMMARY OF THE INVENTION
`the initial loading component and a major proportion of
`According to the present invention, there are pro-
`the secondary loading component.
`In addition,
`the
`vided improved pharmaceutical delivery systems
`working examples include procedures to coat granules
`comprising the secondary loading component with a 35 adapted to provide a therapeutically effective blood
`concentration levels of 7-dimethylamino-6-deoxy-6-
`blended polymer coating composition to give them
`slow release characteristics. The formulations of the
`demethyltetracycline or a non-toxic acid addition salt
`thereof for a sustained period of time of up to about
`twenty-four hours comprising:
`(A) from 51 to 80 parts by weight per 100 parts by
`weight of (A) and (B) combined of an initial load-
`ing therapeutically effective number of quick re-
`lease granules which comprise
`(a) (i) an effective amount of at least one pharma-
`ceutically acceptable excipient; and
`(ii) an effective antibacterial amount of 7-dime-
`thylamino-6-deoxy-6-demethyltetracycline or
`a non-toxic acid addition salt thereof, on or in
`said quick release granules;
`said quick release granules being adapted to release
`substantially completely said tetracycline or salt thereof
`in a medium having a pH of less than about 3.9; and
`(B) from 20 to 49 parts by weight per 100 parts by
`weight of (A) and (B) combined of a secondary
`loading
`therapeutically
`effective
`number of
`blended polymer coated spherical granules which
`comprise
`(a) (i) an independent effective amount of at least
`one
`pharmaceutically
`acceptable
`excipient
`which may be the same as or different than (A)-
`(a)(i); and
`(ii) an independent effective antibacterial amount
`of 7—dirnethylamino-6-deoxy-6-demethyltetra-
`cycline or a non-toxic acid addition salt
`thereof, on or in said coated spherical gran-
`ules; and
`(b) a substantially uniform coating comprising a
`blend of at least two polymers on said coated
`
`copending application are taught to be processable into
`capsule oral dosage unit forms. In vivo data with a
`preferred embodiment of the copending application
`comprising capsules containing 46% of the total dose in
`the form of uncoated quick-release pellets and 54% in
`the form of single polymer (hydroxypropyl methylcel-
`lulose phthalate)-coated slow-release pellets showed
`good bioavailability over 24 hours after a single admin-
`istration, approaching the achieved with two divided
`doses of conventional minocycline tablets.
`It has now been discovered that bioavailability can be
`even more improved by increasing the ratio of quick
`release initial loading pellets to slow release secondary
`loading coated pellets and by using a modified coating
`composition for the latter. Thus, for example, the bi-
`oavailability can be improved by greater than 10% by
`using a major proportion, e.g., 60% of the quick—release
`granules and a minor proportion, e.g., of the slow-
`release granules and providing the latter with a coating
`comprising a small amount of water-soluble polymer in
`the pH-sensitive polymer previously used alone. In
`addition, in multidose studies, the mixed pellet dosage
`forms of the present invention exhibit a surprising reten—
`tion of bioavailability after ingestion of food in compari-
`son with tablets employed in the present state of the art.
`Data are presented hereinafter which show that fed
`subjects had an absorption of 100% of that of the fasted
`subjects with the dosage forms of this invention but
`only 90.6% with the prior art tablets.
`These results are surprising because just the opposite
`would be expected. An early release of most of the
`
`5
`
`10
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`15
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`20
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`
`50
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`60
`
`65
`
`6
`
`

`

`5,348,748
`
`5
`spherical granules (B) one of which is non pH-
`sensitive and rapidly erodible in water and the
`other of which is pH-sensitive and erodible in a
`medium having a pH in the range of from about
`4.5 to about 6.5; said coated spherical granules
`thereby being adapted to release some of said
`tetracycline or salt thereof in a medium having a
`pH in the range of from about 1.0 to about 3.0
`and the remainder rapidly in a medium having a
`pH in the range of from about 4.5 to about 6.5.
`Preferred features of the invention are such pharma-
`ceutical delivery systems in which the quick re-
`lease granules (A) comprise from about 55 to about
`70 parts by weight and the coated granules (B)
`comprise from about 20 to about 45 parts by weight
`per 100 parts by weight of (A) and (B) together,
`and especially those wherein the quick release
`granules (A) comprise about 60 parts by weight
`and the coated granules (B) comprise about 40
`parts by weight per 100 parts by weight of (A) and
`(B) together.
`The invention further contemplates oral dosage units
`in the form of pharmaceutically acceptable liquid carri-
`ers containing the above compositions or systems, hard
`or soft shell capsules at least partially filled with the
`above compositions or systems, and tablets formed from
`the above compositions or systems.
`The invention also provides methods of maintaining a
`therapeutic level of the tetracycline or salt thereof in
`the blood stream of a warm-blooded mammal for about
`
`24 hours comprising administering to the mammal the
`pharmaceutical delivery systems or oral dosage units
`above.
`.
`A method for the preparation of a pharmaceutical
`delivery system is provided comprising the steps of:
`(I) forming an initial loading component by
`(a) blending
`(i) an effective amount of at least one pharmaceu-
`tical acceptable excipient; and
`(ii) an effective antibacterial amount of 7-dime-
`thylamino-6-deoxy-6-demethyltetracycline or
`a non-toxic acid addition salt thereof;
`(b) granulating the resultant blend in the presence
`of a granulating liquid;
`(0) extruding the resultant granulate;
`(d) spheronizing the resultant extrudate to form
`quick release granules which are adapted to re-
`lease substantially completely said tetracycline
`or salt thereof in a medium having a pH of less
`than about 3.9; and
`(e) drying said quick release granules; and
`(II) forming a secondary loading component by
`(a) blending
`(i) an independent amount of at least one phar-
`maceutical acceptable excipient which may be
`the same as or different than (A)(a)(i); and
`(ii) an independent effective antibacterial amount
`of 7-dimethylamino-6-deoxy-6-dernethyltetra—
`cycline or a non-toxic acid addition salt
`thereof;
`(b) granulating the resultant blend in the presence
`of a granulating liquid;
`(c) extruding the resultant granulate;
`(d) spheronizing the resultant extrudate to form
`precursors of coated spherical granules;
`(e) drying said precursors;
`(f) coating said precursors with a substantially uni-
`form coating comprising a blend of at least two
`
`6
`polymers, one of which is non pH-sensitive and
`rapidly erodable in water and the other of which
`is pH-sensitive and erodible in a medium having
`a pH in the range of from about 4.5 to about 6.5
`and
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`60
`
`65
`
`(B) preparing therefrom a controlled release pharma-
`ceutical composition in oral dosage unit form by
`the step of at least partially filling a hard or a soft
`shell capsule with a pharmaceutical delivery sys-
`tem with from about 51 to about 80 parts by weight
`of the quick release granules prepared by steps (I)
`and from about 20 to about 49 parts by weight of
`the slow release granules produced by the steps (11)
`and optionally sealing said capsules.
`Preferred features of the invention comprise such a
`method wherein the capsule is filled with from about 55 '
`to about 70 parts by weight of the quick release gran-
`ules prepared by steps (I) and from about 30 to about 45
`parts by weight of the coated granules prepared by
`steps (11), per 100 parts by weight of said granules and
`especially preferred is such a method wherein the cap-
`sule is filled with about 60 parts by weight of the quick
`release granules prepared by steps (I) and about 40 parts
`by weight of the coated granules prepared by steps (11),
`per 100 parts by weight of the granules.
`The pharmaceutical delivery systems and the capsule
`oral dosage unit forms described above provide once-a-
`day prolonged effect controlled release forms of mino-
`cycline which maintain improved therapeutic blood
`levels for periods of up to twenty-four hours resulting in
`desirable and effective antibacterial therapy and less
`frequent administration to a subject. They also avoid
`high local concentrations in a system which may cause
`side effects such as gastroirritability.
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`Novel pharmaceutical delivery systems have been
`discovered comprising mixed blends of an initial load-
`ing therapeutically effective number of quick-release
`granules and a secondary loading therapeutically effec-
`tive number of blended polymer coated spherical gran~
`ules. These systems and compositions can be filled into
`capsules to prepare oral dosage units. Many benefits can
`be realized from these novel delivery systems and oral
`dosage unit forms over conventional controlled release
`formulations. They result in a superior controlled and
`prolonged delivery of minocycline to a subject which in
`turn results in the achievment of once-a—day dosages of
`7-dimethylamino-6-deoxy-6-demethy1tetracycline
`or
`non-toxic acid addition salts thereof in the compositions
`and oral dosage unit forms to sustain a desired blood
`level concentration in a subject for a relatively long
`period of time of up to twenty-four hours. Therefore,
`less frequent administration of the minocycline com-
`pound to a subject, possibly fewer and lessened side
`effects, including reduced gastroirritability, and better
`subject compliance with a medicament regimen are
`possible.
`Oral dosage unit forms are those which are orally
`administered and contain medicaments which are ab-
`sorbed into the blood stream from the alimentary tract.
`An initial loading therapeutically effective amount or
`number of quick release granules is that amount or num-
`ber which provides an immediate or rapid and substan-
`tially complete release in a medium having a pH of less
`than about 3.9 and, preferably in a range of from about
`1.0 to about 2.5, such as in the human stomach and
`
`7
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`7
`thereby delivers and maintains a recommended dosage
`or concentration level of 7—dimethyamino-6-deoxy-6-
`demethytetracycline or a non-toxic acid addition salt
`thereof to the blood stream or plasma of a subject.
`within a recommended period of time and maintains
`that level or a further recommended level for a further
`
`recommended period of time. This provides a first pulse
`of minocycline, preferably in the stomach, which
`quickly attains therapeutic plasma drug levels, i.e. at
`least that amount determined by in vivo clinical evalua-
`tion or in vitro microbiological assay to treat success—
`fully infections caused by the invading organism or
`organisms.
`effective
`therapeutically
`loading
`A secondary
`amount or number of blended polymer coated spherical
`granules is that amount or number which provides a
`slow release of a small amount in the stomach and a
`
`complete release in a medium having a pH in the range
`of from about 4.0 to about 7.5 and preferably from about
`4.0 to about 6, as in the human upper intestinal tract and
`particularly in the duodenum/jejunem. The use of a
`higher level of quick release granules in proportion to
`delayed release granules is believed to result in a higher
`absorption of minocycline because minocycline is pref—
`erentially absorbed in the duodenum and jejunem. It
`thereby delivers and maintains a further recommended
`dosage or concentration level of 7-dimethylamino-6-
`deoxy-6-demethyltetracycline or a non-toxic acid addi-
`tion salt thereof to the blood stream or plasma of a
`subject within an independent recommended period of
`time and maintains that level or a different recom-
`
`mended level for an independent additional recom-
`mended period of time. This second pulse provides a
`delayed release and a controlled release of minocycline,
`preferably in the duodenum, which extends therapeutic
`plasma drug levels initially achieved by the first pulse,
`i.e. at least that amount determined effective for the
`particular organism causing the infection as described
`above, for a total prolonged period of time, i.e. up to
`about 24 hours.
`The initial loading of the minocycline is achieved by
`the administration of quick release granules containing
`the minocycline. The secondary loading can mixed
`blends of initial loading and secondary loading compo-
`nents. The total period of time this therapeutic plasma
`drug level is maintained from the combined effect of the
`two different types of granules is preferably about 24
`hours. Therefore, only one dosage unit will provide
`effective antimicrobial therapy for an entire day, the
`total therapeutic amount, i.e. the initial loading thera-
`peutically effective amount or number plus the second-
`ary loading therapeutically effective number, being that
`amount and/or number which will achieve and will
`maintain at least a therapeutically effective concentra-
`tion of 7-dimethy1amino-6-deoxy-6—demethyltetracy-
`cline or a non-toxic acid addition salt thereof/m1 of
`serum or plasma in the blood serum or plasma of a
`human subject for about 24 hours.
`The salts of minocycline useful in the present inven—
`tion are the non-toxic acid addition salts, e.g. sulfonic,
`trichloroacetic, hydrochloric acid salts.
`The last named compound is also known as minocy-
`cline hydrochloride. Typically, minocycline hydro-
`chloride has been administered orally in a daily dosage
`of about 100 to about 400 mg in at least two and often
`more divided doses a day in a normal adult human
`being. It is commercially available in many forms under
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`60
`
`65
`
`5,348,748
`
`8
`the trademark Minocin from Lederle Laboratories,
`Wayne, NJ. (PDR 44th Ed.).
`It should additionally be noted that minocycline hy-
`drochloride readily undergoes epimerization and oxida-
`tive degradation to epiminocycline, a pharmacologi—
`cally inactive and undesirable tetracycline compound.
`The amount of the epimer should be minimal but may
`range as high as from about 1.5 percent to about 10
`percent without affecting the intended once daily dose
`of the present invention.
`Preferably, the pharmaceutical delivery systems and
`oral dosage unit forms of the present invention will
`contain from about 25 mg to about 400 mg of 7-dime-
`thylamino-6-deoxy-6-demethyltetracycline or non-toxic
`acid addition salt thereof and most preferably from
`about 80 mg to about 280 mg. The ratio of initial loading
`component,
`i.e. minocycline powder, quick release
`granules, quick release coating or the like, to the sec-
`ondary loading component,
`i.e. blended polymer-
`coated spherical granules or single coated core, ranges
`from about 51:80 to about 20:49 parts by weight of
`initial loading component and secondary loading com—
`ponent combined and preferably from about 55:70 to
`about 30:45. Preferably, the initial loading component,
`the secondary loading component, or both indepen-
`dently contain from about 20 to about 200 mg of mino-
`cycline.
`The rapid and substantially complete release of the
`initial loading component is such that the initial loading
`component releases greater than about 70 percent and
`preferably greater than about 80 percent of the minocy-
`cline in less than about 90 minutes and preferably less
`than about 60 minutes in a medium of aqueous buffer,
`e.g. hydrochloric acid and/or acetate buffer, having a
`pH of less than about 3.9. Therefore, any optional poly-
`mer coating on the initial loading component must be
`specifically rapidly and substantially erodible or dis-
`solvable to permit the initial loading component to meet
`these conditions.
`The rapid and substantially complete release of the
`secondary loading component core is such that the
`secondary loading component or single coated core
`releases greater than about 40 percent and preferably
`greater than about 70 percent of the minocycline in less
`than about 90 minutes in a medium of aqueous buffer,
`e.g. acetate and/or phosphate buffer, having a pH in the
`range of from about 4.5 to about 6.5. Therefore, the
`blended polymer coating must be both partially water-
`soluble and thereafter specifically rapidly and substan-
`tially completely erodible or dissolvable at the specified
`pH range to permit the secondary loading component
`to meet these conditions.
`Further preferred embodiments of the present inven-
`tion provide additionally that either from about 5 to
`about 20 percent of the minocycline in the secondary
`loading component is released in about 2 hours when
`suspended in a medium of simulated gastric fluid having
`a pH of about 1.2 at about 37° C. or from about 20 to
`about 50 percent of the minocycline in the secondary
`loading component is released in about 2 hours when
`suspended in a medium of simulated gastric fluid having
`a pH of about 1.2 at about 37° C.
`The drug is released when it may be determined by a
`standard assay.
`Many pharmaceutical excipients will be suitable for
`use in this invention. Judicious selection will be easy
`with the requirements and the test procedures men-
`tioned herein kept in mind. An excipient with a known
`
`8
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`

`

`9
`degree of solubility in water and solubility and swella-
`bility in the respective juices of the stomach and the
`upper
`small
`intestine, particularly the duodenum,
`should be used. Such excipients in either the quick re-
`lease granules, the slow release blended polymer coated
`spherical granules, or a combination of any of the fore-
`going include lactose, other mono- or di—saccharides,
`microcrystalline cellulose,
`starch,
`sodium carboxy-
`methyl cellulose, hydroxypropyl cellulose, hydroxy-
`ethyl cellulose, crosscarmellose sodium, pregelatinized
`starch, polyvinylpyrrolidone, cross-linked polyvinyl-
`pyrrolidone, hydroxypropyl methylcellulose, cellulose
`acetate, hydroxypropyl methylcellulose phthalate, pol-
`yvinyl acetate phthalate, microcrystalline cellulose in
`combination with lactose, microcrystalline cellulose in
`combination with sodium carboxymethyl cellulose,
`microcrystalline cellulose in combination with crosscar—
`mellose sodium, mixtures of any of the foregoing and
`the like as well as others with which those of ordinary
`skill in the art will be familiar, most of which are listed
`in standard references, for example, Remington’s Phar-
`maceutical Sciences, 1985, 17th Edition, Philadelphia
`College of Pharmacy and Science, Chapter 68, Pharma-
`ceutical Necessities, pages