FIELD OF THE INVENTION
This invention relates to the pharmaceutical composition comprising of one or more
drugs of tetracycline class of antibiotics and Polyalkylene oxide polymers for controlled
release used for the treatment of acne vulgaris, commonly known simply as "acne."
Acne is a disease of the skin in which the pilosebaceous structures of the skin become
inflamed, leading to the formation of comedones, pustules and nodules. Acne can lead
to permanent scarring in severe cases.
It is generally believed that acne arises when hyperkeratosis of the pilosebaceous
structure wholly or partially blocks the opening of the structure, resulting in comedones
filled with sebum, keratin, and Propionibacterium acnes. These lesions are commonly
identified as acne. P. Acnes naturally occurs in normal skin, but is especially and
characteristically present in acne lesions. It is believed that metabolic byproducts and
waste from P. acnes within the pilosebaceous structures cause or contribute to the
inflammation of acne lesions.
Conventional acne treatments have taken many forms. Topical keratolytic agents, such
as salicylic acid are sometimes used. Keratolytic agents are thought to encourage the
opening up of blocked pilosebaceous structures, thereby reducing conditions that are
favorable to inflammation. Benzoyl peroxide, an anti-microbial, remains a popular and
effective treatment. Topical antibiotics, such as clindamycin, which are effective against
P. acnes, have also been used with a view towards preventing the formation of
metabolic byproducts from this organism. Topical retinoids such as tretinoin have also
been used in the treatment of acne.
Systemic (i.e. non-topical) treatments for acne include the use of oral antibiotics in more
serious cases. These treatments are directed towards the reduction in the amount P.
acnes in the skin, especially the pilosebaceous structures, and seek to reduce the
inflammation caused by waste materials and metabolic byproducts from these
organisms. Tetracycline and macrolides antibiotics are most commonly used for this
purpose. These include tetracycline, Erythromycin, minocycline and doxycycline.
Standard oral minocycline therapy for acne in pediatric patients calls for the
administration of a 4 mg/kg initial loading dose, and a 2-mg/kg dose every 12 hours
2

thereafter. This results in a dose of 6 mg/kg on the first day of treatment and a 4-mg/kg
dose each day thereafter. In adults, a 200 mg initial dose is followed by a 100 mg dose
every 12 hours thereafter. In a typical patient, this results in about a 4.5-mg/kg dose on
the first day of treatment, and 3.0-mg/kg dose each day thereafter.
In cases where acne does not respond to oral antibiotic treatment, oral isotretinoin is
sometimes used. While effective, isotretinoin is also powerfully teratogenic, and women
of childbearing age are required to use multiple methods of contraception while taking
the drug.
While oral tetracycline antibiotics remain a highly favored and widely used treatment for
more serious cases of acne, it is not without side effects. Vestibular side effects,
including extreme dizziness and concomitant nausea, can be so severe as to result in
discontinuance of tetracycline therapy. Long-term use can sometimes result in vaginal
candidisis, esophageal erosions and in antibiotic resistant infections.
Vestibular reactions are an undesirable and sometimes seriously disconcerting side
effect of minocycline therapy. According to the present invention, it is possible to provide
persons susceptible to such side effects with the benefits of minocycline therapy while
diminishing the incidence and/or severity of these side effects. This is accomplished by
adjusting the controlled release of the minocycline dosage form so that, while an
effective concentration of minocycline is achieved in the blood stream of the patient,
vestibular side effects are greatly reduced.
The US patent number 5908838 discloses the prevention or subside the vestibular side
effects of minocycline in the treatment of acne by the administration of slow dissolving
minocycline once a day formulation.
The US application number 20060293290 discloses the dose of the minocycline of 0.5-
1.5 mg per kg body weight in order to prevent adverse side effects of the minocycline
conventional dose
The PCT application number 2004078111 discloses an extended release composition of
minocycline containing two celluloses derivatives, which differ in the viscosities
3

Another PCT application number discloses a non-spheronized, multiparticulate modified
release pharmaceutical composition comprising: a core comprising: a) an effective
antibacterial amount of minocycline or its salts thereof, b) at least one pharmaceutically
acceptable excipient, a pH sensitive coating; and optionally, one or more
pharmaceutically acceptable excipients.
SUMMARY OF THE INVENTION
The controlled release composition of the present invention is provided by the use of
matrix of the polymers like alginic acid, salts of alginic acid, polyalkylene polymers,
carbopol or the combinations there of.
OBJECTIVES OF THE INVENTION
The main objective of the invention is to formulate a controlled release dosage form of
one or more tetracycline antibiotics with the use of matrix made of release controlling
agents like alginic acids or its salts, polyalkylene oxide polymers, carbopol with / without
loading dose.
Another objective of the invention is to use controlled release dosage form of
minocycline for the treatment of skin diseases/disorders like acne, dermatitis,
telangiectasia, rosacea and the like.
One more objective of the invention is to obtain a controlled release of minocycline with
matrix of polyalkylene oxide polymers; optionally coated with coating agents.
Another objective of the invention is to prepare controlled release dosage form of
minocycline by the use of one or more polymers extra granular or intra granular, to
achieve the controlled release.
Yet another objective of the invention is to achieve the controlled release of Minocycline
by the use of combination of two are more polymers in specific ratio to retard the release
of the minocycline.
4

DETAILED DESCRIPTION OF THE INVENTION
According to the present invention the oral controlled release delivery system of one or
more tetracycline antibiotic for the treatment of skin diseases acne, dermatitis,
telangiectasia, rosacea and the like. The controlled release of the Minocycline is
achieved by the use of the polymer matrix of the one are more polymers. The Controlled
releasing polymers used in this invention are selected from the group of alginic acid, salt
of alginic acid (like sodium alginate), polyalkylene polymers (like polyethylene oxide) but
not limited to these examples. The present invention also includes the combination two
or more polymers.
Dosage forms include, but are not limited to tablets, pellets, minitablets, capsules,
troches, lozenges, dispersions, suspensions, suppositories, ointments, cataplasms,
pastes, powders, creams, solutions, capsules (including encapsulated spheroids), and
patches.
The dosage forms may also include immediate release as well as formulations adapted
for controlled, sustained, extended, or delayed release. Most preferably tablets and
capsules are the dosage form. Tablets and spheroids may be coated by standard
aqueous and nonaqueous techniques as required.
The dosage form of the present invention may be administered once a day twice a day
or once weekly and twice weekly.
The polyalkylene polymers covers poly (propylene oxide), poly (ethylene oxide) have the
molecular weight in the range of 100,000 to 7,000,000 and viscosities in the range of 30-
17,600 cps the viscosity mentioned above are measured for the solutions of 1-10%
preferably 1-5%
As used herein, the term "pharmaceutically acceptable salts" refers to salts prepared
from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic
acids. Suitable non-toxic acids include inorganic and organic acids such as acetic,
benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic,
5

glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic,
methanesulfonic, mucic, nitric, palmoic, pantothenic, phosphoric, succinic, sulfuric,
tartaric acid, p-toluenesulfonic and the like. Particularly preferred are hydrochloric,
hydrobromic, phosphoric, and sulfuric acids, and most particularly preferred is the
hydrochloride salt.
In an embodiment of the present invention, the hard gelatin capsule may comprises of
mini-tablets. These mini-tablets comprise of active ingredient, binder and water-soluble
component and optionally conventional excipients. These mini-tablets are coated with
combination of water-soluble and waters insoluble polymers.
The term "granulation methods" may include dry and wet granulation process where in
the wet granulation process may include an aqueous and non aqueous or combination,
the granulation process may also include compaction, direct compression or melt
granulation techinqe which may include extrusions and spheronization,
The term "carriers" may include excepients, diluents, polymers which may include
hydrophilic or hydrophobic polymers and combination there of and the like.
The term "modified release" may consist of sustained release, prolonged release,
delayed release, controlled release and the like.
The scope of the present invention is not limited to hard gelatin capsules. The scope of
the invention includes cellulose capsules or any capsule known to the person skilled in
the art.
The present formulations may optionally contain a surface-active agent. The preferred
agent is polaxamer. However, other agents may also be employed such as dioctyl
sodium sulfosuccinate (DSS), triethanolamine, sodium lauryl sulphate (SLS),
polyoxyethylene sorbitan and poloxalkol derivatives, quaternary ammonium salts or
other pharmaceutically acceptable surface-active agents known to one ordinary skilled in
the art.
The pharmaceutical formulation according to the present invention include but is not
limited to tablets (single layered tablets, multilayered tablets, mini tablets, bioadhesive
tablets, caplets, matrix tablets, tablet within a tablet, mucoadhesive tablets, modified
6

release tablets, pulsatile release tablets, timed release tablets), pellets, beads, granules,
sustained release formulations, capsules, microcapsules, tablets in capsules and
microspheres, matrix formulations, microencapsulation and powder/pellets/granules for
suspension.
According to the embodiment of the present invention, the mini-tablet contains polyvinyl
pyrrolidone as binder. Polyvinylpyrrolidone may be present in an amount from about
0.5% to about 60%, preferably from about 2% to about 25% by weight, of the total
weight of extended release composition.
In addition to the above ingredients, pharmaceutical grade magnesium stearate/stearic
acid as a glidant, talc as an anti-adherent and colloidal silicon dioxide as a lubricant are
included in the mini-tablet. Preferably, magnesium stearate/stearic acid, talc and
colloidal silicon dioxide are present in amounts in the range of 0.5% to 25% by weight
either alone or in combination.
The pharmaceutical formulations according to the invention can be prepared by use of
well known pharmaceutical processing techniques such as blending, granulation, milling,
spray drying, compaction, or coating.
The scope of the invention may also includes polysaccharides like gums, and their
derivative and waxes know in the prior art
In another embodiment, the present invention provides for the use of multiparticulate
formulations of the invention in the preparation of medicaments for delivery to a pediatric
or geriatric patient
The present invention involves drug loading in the formulation is done by different
methods like:
• Co blending the drug with fillers
• Encapsulation of the drug along with polymer
• Coating of inter core with drug solution or dispersion
• Multiple layering of the drug on a inert core with intermediate release modifying
polymers layers which may be enteric or water soluble and/or water insoluble polymers
with or with out seal coating.
7

• Compression coating
The scope of the invention may not be limited to the methods disclosed above but also
extents to the process known in the art. The present invention involves process by which
tetracycline present in an amount from 10 to 200mg the drug is mixed with suitable
excipients, preferably minocycline in the range of 45 to 135mg.
Another scope of the present invention is to prepare a pharmaceutical dosage form
comprising minocycline with/with out loading dose and maintenance dose. The loading
may be present in the range of 0 to 30mg and maintenance dose in the range of 45 to
135mg, the maintenance dose of minocycline may be present in the form of granular
form or a compressed form, which are optionally coated.
Another embodiment of the present invention involves preparation of single or
multilayered tablet where in the multilayered tablet may consist of an immediate release
layer and modified release layer.
Binders suitable for use in pharmaceutical compositions and dosage forms include, but
are not limited to, corn starch, potato starch, or other starches, gelatin, natural and
synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered
tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose
acetate, carboxymethyl cellulose, sodium carboxymethyl cellulose), polyvinyl
pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose,
(e.g., Nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof. The
binder or excipients may also include organic acid derivatives like citric acid or it salts.
Lubricants may be selected from, but are not limited to, those conventionally known in
the art such as Mg, Al or Zn stearate, polyethylene glycol, glyceryl behenate, mineral oil,
sodium stearyl fumarate, stearic acid, hydrogenated vegetable oil, talc and the like.
Glidants include, but are not limited to, silicon dioxide; magnesium trisilicate, powdered
cellulose, starch, talc and tribasic magnesium silicate, colloidal silicon dioxide, silicon
hydrogel and mixtures thereof, and other materials known to one of ordinary skill in the
art. The binder/filler in pharmaceutical compositions of the present invention is typically
present in about 50 to about 99 weight percent of the pharmaceutical composition.
8

Disintegrants that can be used to form pharmaceutical compositions and dosage forms
of the invention include, but are not limited to, agar-agar, alginic acid, microcrystalline
cellulose, croscarinellose sodium, crospovidone, polacrilin potassium, sodium starch
glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches,
clays, alginic acid derivatives, other celluloses, gums or mixtures thereof.
Lubricants which can be used to form pharmaceutical compositions and dosage forms of
the invention include, but are not limited to, magnesium stearate, mineral oil, light
mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid,
sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil,
sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate,
ethyl laureate, agar, or mixtures thereof. A lubricant can optionally be added, typically in
an amount of less than about 1% w/w of the pharmaceutical composition.
The controlled release polymers or release controlling agents can be hydrophilic,
hydrophobic or combination thereof. The hydrophilic rate-controlling polymer includes
but is not limited to hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl
Methylcellulose, sodium carboxymethyl cellulose, sodium alginate, carbomer
(Carbopol(TM)), xanthan gum, guar gum, locust bean gum, poly vinyl acetate, polyvinyl
alcohol. Preferably the rate-controlling polymer is hydroxypropylmethylcellulose (Low
viscosity grade). The hydrophobic rate controlling agent in matrix includes but are not
limited to hydrogenated vegetable oil, but other suitable agents include purified grades of
beeswax; fatty acids; long chain fatty alcohols, such as cetyl alcohol, myristyl alcohol,
and stearyl alcohol; glycerides such as glyceryl esters of fatty acids like glyceryl
monostearate, glyceryl distearate, glyceryl esters of hydrogenated castor oil and the like;
oils such as mineral oil and the like, or acetylated glycerides; ethyl cellulose,stearic acid ,
paraffin, camauba wax, talc; and the stearate salts such as magnesium, zinc and other
materials known to one of ordinary skill in the art. Polymers according to the present
invention may include controlled release, sustain release, delayed release, modified
release, immediate release and the like.
In embodiments of the present invention, a pharmaceutical composition comprises an
active agent and atleast one or more polymer. Polymers include, but are not limited to, a
crosslinked poly(acrylic acid), a poly(alkylene oxide), a polyvinyl alcohol), a polyvinyl
pyrrolidone); a polyurethane hydrogel, a maleic anhydride polymer, such as a maleic
9

anhydride copolymer, a cellulose polymer, a polysaccharide, starch, and starch based
polymers.
Coating agents which are useful in the coating process, include, but are not limited to,
polysaccharides such as maltodextrin, alkyl celluloses such as methyl or ethyl cellulose,
hydroxyalkylcelluloses (e.g. hydroxypropylcellulose or hydroxypropylmethylcelluloses);
polyvinylpyrrolidone, acacia, corn, sucrose, gelatin,shellac, cellulose acetate pthalate,
lipids, synthetic resins,acrylic polymers, polyvinyl alcohol (PVA), copolymers of
vinylpyrrolidone and vinyl acetate (e.g. marketed under the brand name of Plasdone)
and polymers based on methacrylic acid such as those marketed under the brand name
of Eudragit. These may be applied from aqueous or non-aqueous systems or
combinations of aqueous and non-aqueous systems as appropriate. The scope of the
invention is not limited to coating agents disclosed above, it may include other polymers
known in the art.
Additives can be included along with the film formers to obtain satisfactory films. These
additives can include plasticizers such as dibutyl phthalate, triethyl citrate, polyethylene
glycol (PEG) and the like, antitacking agents such as talc, stearic acid, magnesium
stearate and colloidal silicon dioxide and the like, surfactants such as polysorbates and
sodium lauryl sulphate,fillers such as talc, precipitated Polishing agents such as
Beeswax, camauba wax, synthetic chlorinated wax and opacifying agents such as
titanium dioxide and the like. All these excipients can be used at levels well known to the
persons skilled in the art.
Pharmaceutical dosage forms of the invention can be coated by a wide variety of
methods. Suitable methods include compression coating, coating in a fluidized bed or a
pan and hot melt (extrusion) coating. Such methods are well known to those skilled in
the art.
The invention is further defined by reference to the following examples describing in
detail the preparation of the compositions of the invention. It will be apparent to those
skilled in the art that many modifications, both to materials and methods, may be
practiced without departing from the purpose and interest of this invention.
10

EXAMPLE: 1

NAME OF THE INGREDIENT % / Tablet
Intra granular
Minocycline HCI 39
Microcrystalline cellulose 47.5
Polyethylene oxide 8.3
Colloidal silicon dioxide 0.97
Magnesium stearate 0.97
Extra granular
Colloidal silicon dioxide 0.5
Magnesium Stearate 0.1
Film coating qs
Procedure: Minocycline HCI, Microcrystalline Cellulose, polyethylene oxide, and
Colloidal silicon dioxide blended and then mixed with Magnesium Stearate, granulated
the above material by dry granulation then lubricated and compressed, the compressed
tablets are coated with a flim coating
DISSOLUTION PROFILE

Time % RELEASE
30 5-30
60 20-40
90 30-50
120 45-65
150 60-85
180 NLT 80%
EXAMPLE II

NAME OF THE INGREDIENT % / Tablet
CORE COMPOSITION
Minocycline HCI 38.0
Microcrystalline cellulose 47
11

Carbopol 9.1
Colloidal silicon dioxide 0.97
Magnesium stearate 0.97
Colloidal silicon dioxide 0.1
Magnesium Sterate 0.97
Film coating qs
Procedure: Minocycline HCI, Microcrystalline Cellulose, Carbopol, and Colloidal silicon
dioxide blended and then mixed with Magnesium Stearate, granulated the above
material by dry granulation then lubricated and compressed, the compressed tablets are
coated with a flim coating
EXAMPLE III

NAME OF THE INGREDIENT % per tablet
CORE COMPOSITION
Minocycline HCI 36.72
Microcrystalline cellulose 47.2
Colloidal silicon dioxide 0.96
Magnesium stearate 0.96
Carbopol 10.0
Colloidal silicon dioxide 0.97
Magnesium Sterate 0.97
Film coating qs
Procedure: Minocycline HCI, Microcrystalline Cellulose, and Colloidal silicon dioxide
blended and then mixed with Magnesium Stearate, granulated the above material by dry
granulation to the granules Carbopol, was added then lubricated and compressed, the
compressed tablets are coated with a flim coating
EXAMPLE IV

NAME OF THE INGREDIENT % per tablet
Minocycline HCI 37.36
Microcrystalline cellulose 35.5
Sodium alginate 20.5
12


Procedure: Minocycline HCI, Microcrystalline Cellulose, Sodium alginate, and Colloidal
silicon dioxide blended and then mixed with Magnesium Stearate, granulated the above
material by dry granulation then lubricated and compressed, the compressed tablets.
EXAMPLE V

Procedure: Minocycline HCI, Microcrystalline Cellulose, Sodium alginate, Polyethylene
oxide and Colloidal silicon dioxide blended and then mixed with Magnesium Stearate,
granulated the above material by dry granulation then lubricated and compressed in to
tablets.
EXAMPLE VI

13


Procedure: Minocycline HCI, Microcrystalline Cellulose, Sodium alginate, Carbopol and
Colloidal silicon dioxide blended and then mixed with Magnesium Stearate, granulated
the above material by dry granulation then lubricated and compressed into tablets
EXAMPLE VII

Procedure: Minocycline HCI, Microcrystalline Cellulose, polyethylene oxide, and
Colloidal silicon dioxide blended and then mixed with Magnesium Stearate, granulated
the above material by dry granulation then lubricated are coated with a flim coating and
filled in capsule.
EXAMPLE VIM

14


Procedure: Minocycline HCI, Microcrystalline Cellulose, Polyethylene oxide and
Colloidal silicon dioxide blended and granulated in rapid mixture granulator with water
the granule optained are dried and mixed with colloidal silicon dioxide, lubricated with
Magnesium Stearate, and compressed, the compressed into minitablets are coated with
a flim coating and filled in capsule.
EXAMPLE IX

Procedure: Minocycline HCI, Microcrystalline Cellulose and Colloidal silicon dioxide
blended and granulated by melt granulation the PEO granule obtained are mixed with
colloidal silicon dioxide, lubricated with Magnesium Stearate, and compressed, the
compressed tablets are coated with a flim coating
15

EXAMPLE X

Procedure: Minocycline HCI, Microcrystalline Cellulose and Colloidal silicon dioxide
blended and granulated the PEO granule obtained are mixed with Minocycline HCI,
colloidal silicon dioxide, lubricated with Magnesium Stearate, and compressed, the
compressed tablets are coated with a flim coating
16

We claim:
1. A pharmaceutical composition comprising minocycline or its salts and one or
more polymers selected from the group comprising of polyalkyleneoxide, alginic
acid or its salts and one or more pharmaceutically acceptable carriers.
2. The pharmaceutical composition-according claim 1 wherein the Minocycline is
10-80% of the pharmaceutical dosage form.
3. The pharmaceutical composition according claim 1 where the polymer is in the
concentration of about 5-50% of the pharmaceutical composition.
4. The pharmaceutical composition according to claim 1 where is in the composition
is a immediate release and /or modified release
5. A modified release dosage form comprising minocycline or its salts, one or more
polymers selected from the group consisting of polyalkyleneoxide, salts of alginic
acid and one or more pharmaceutically acceptable.
6. The modified release formulation according to claim 5 may be with or with out
loading dose.
7. The modified release dosage form according to claim 5 where in the dosage form
is in the form of pellets, granules or mini tablets filled in the capsule or
compressed in to tablets.
8. A modified release dosage form comprising (a) initial loading dose of
therapeutically effective amount of minocycline or its salts, one or more
pharmaceutically acceptable carriers and/or (b) a maintenance dose of
minocycline or its salts, controlled release polymers selected from the group
consisting of polyalkyleneoxide, salts of alginic acid and one or more
pharmaceutically acceptable carriers.
17

18
9. A modified release dosage form consisting of minocycline or its salts and
polyethylene oxide and one or more pharmaceutically acceptable carrier
optionally coated with coating agents.
10. A modified release dosage form consisting Minocycline or its salts, polyethylene
oxide and alginic acid or its salts and one or more pharmaceutically acceptable
carrier optionally coated with coating agents.
11. The release dosage form according to claim 9 where is in the polyethylene oxide
is added extra granular or intra granular.
12. A process of preparation of the modified release tablet comprises the following
steps of: granulating minocycline or its salts, one or more diluents and a lubricant
followed by addition of the polymer to the granules, the granules obtained are
compressed into mini tablets then fill in to capsules or punched into tablets.

A pharmaceutical composition comprising minocycline or its salts and one or
more polymers selected from the group comprising of polyalkyleneoxide, alginic
acid or its salts and one or more pharmaceutically acceptable carriers.