Field of the Invention
The present invention relates to improvements in stability, a single coat modified release
preparations, such as modified release pharmaceutical preparations.
Background of the Invention
Modified release preparations are those that provide an in-vitro & in-vivo release profile
(a 'modified release') of an active ingredient, such as a pharmaceutically active
ingredient, that is different from the in-vitro & in-vivo release profile of the active
ingredient without the modification (an 'immediate release'). The modified release may
be such as a delayed, extended, pulsed or sustained release. The modification of the
release may be desired for a number of reasons, such as for minimizing the side effects of
the drug or for decreasing the frequency of dosing to improve patient compliance.
As with all pharmaceutical preparations, an important aspect of the manufacture of
modified release preparations is their stability over extended periods of time, which is
often referred to as 'shelf life'. Typically, a preparation's shelf life is linked to two
aspects; firstly, the stability of the ingredients themselves, namely the maintenance of
their chemical, microbiological, therapeutic and toxicological properties over time, and
secondly, the maintenance over time of the originally intended rate of drug release from
the dosage form. The present invention is directed towards this both the aspects of
stability. In the first aspect of the stability, the present invention has been made to
overcome the problems associated previously with doxycycline hyclate.
All pharmaceuticals must have an appropriate shelf life, being the time for which it can
be guaranteed that the preparation has the same properties that it had at the time it was
manufactured. These properties may be such as impurity content, drug degradants or rate
of drug release. For oral preparations, this shelf life is usually at least 18 months.
The recommended dose of doxycycline is 100 mg three times a day (300 mg/day) for the
treatment of diseases associated with bacterial and viral infections. Doxycycline at doses

of 40 mg/day is recommended for the treatment of inflammatory papules, pustules in-
patient with Rosacea.
To maintain reasonably stable plasma concentrations, it is necessary to resort to frequent
dosing, and the resulting inconvenience to the patient often results in lowered compliance
with the prescribed dosing regimen. Moreover, widely fluctuating plasma concentrations
of the drug may result in administration of less than therapeutic amounts of the drug in a
conservative dosing regimen, or amounts too large for the particular patient in an
aggressive dosing regimen.
The convenience of once daily dosing generally improves patient compliance, especially
for elderly patients and for patients taking multiple medications. Once per day dosing
may also lessen or prevent potentially undesirable dose-related effects by reducing peak
blood levels (Cmax) and, may also increase drug efficacy by increasing minimum plasma
concentrations (Cmin).
Once daily dosing of doxycycline, however, presents numerous challenges as
doxycycline is not absorbed uniformly in the gastrointestinal (Gl) tract. Doxycycline is
absorbed in the small intestine and in the ascending colon in humans, but is poorly
absorbed beyond the hepatic flexure, thereby suggesting that the mean absorption
window for doxycycline is, on average, about six hours or less - any drug release from a
conventional ER dosage form beyond six hours would thus be wasted because the dosage
form has traveled beyond the hepatic flexure.
Various approaches have been tried out for developing a once daily dosage form of
doxycycline.
US 6,958,161 B2 relates to a modified release preparation having one or more coated
core elements, each core element including an active ingredient and having a modified
release coating, wherein a stabilizing coat is provided between each core element and its
modified release coating so that, upon in vitro dissolution testing, the amount of active
ingredient released at any time on a post-storage dissolution profile is within 40

percentage points of the amount of active ingredient released at any time on a pre-storage
dissolution profile.
US 6,30,320 B2 relates to an antibiotic product, in particular a tetracycline, such as
doxycycline, is comprised of at least three dosages forms, each of which has a different
release profile, with the Cmax for the antibiotic product being reached in less than about
twelve hours. In one embodiment, there is an immediate release dosage form, as well as
two or more delayed release dosage forms, with each of the dosage forms having a
different release profile, wherein each reaches a Cmax at different times.
US 2004/0228915 A1 is directed to an extended release multiparticulate formulation of a
therapeutic agent, wherein coated core multiparticulate particles of the therapeutic agent
are overcoated with a binder-dispersing agent, such as povidone or cross-povidone. The
binder-dispersing agent in the formulations of the present invention ensure that
compressed tablets formed therefrom will remain intact through oral administration, and
dissolve shortly thereafter, enabling the multiparticulates to release the therapeutic agent
contained therein over an extended period of time.
US 2003/0180362 Al relates to a multi-stage oral drug controlled-release system
involves the stepwise release of drug-containing granules from an inner matrix, which is
surrounded by a coating or release-modifying layer. The granules contain an active drug
and a carrier material in size of 0.1-1 mm. The carrier material is hydrophobic when the
drug has a water-solubility of 1 mg/ml or more, and is hydrophilic when the drug has a
water-solubility of less than 1 mg/ml. The inner matrix, in which the drug-containing
granules are embedded, is formed from swelling and erodible polymer(s) and swelling-
regulating material(s). The release-modifying layer is composed of a hydrophobic
release-modifying polymer, a hydrophilic release-modifying polymer, pH-dependent
release-modifying polymer or mixtures thereof.
Doxycycline hyclate is a yellow crystalline powder soluble in water and in solutions of
alkali hydroxides and carbonates. Doxycycline has a high degree of lipid solubility and a

low affinity for calcium binding. It is highly stable in normal human serum. Doxycycline
will not degrade into an epianhydro form.
Most of the above-mentioned patent applications disclose controlled delivery systems,
which utilize hydrophilic, polymeric matrices. However, for highly soluble drugs, such
matrices do not provide adequate control over the drug release rate, instead resulting in a
release that approximates first-order kinetics.
Thus there is need to develop stable controlled release compositions of doxycycline,
which provide complete drug release and afford stable plasma levels in a once-a-day
dosing regimen using hydrophobic and hydrophilic release controlling agent(s).
A further aspect of the invention provides a solid dosage form, such as a tablet, capsules
pellets, tablet filled in capsule, minitablets filled in capsule, granules, powders and
microtablets that are adapted for once daily oral dosing.
Object of the Invention
The controlled release pharmaceutical compositions comprising doxycycline of present
invention may employ any pharmaceutically acceptable form of doxycycline including
base or its pharmaceutically acceptable complexes, salts, polymorphs, hydrates, solvates,
enantiomers or racemates.
Therefore, the first object of the present invention provides a controlled release
pharmaceutical compositions comprising therapeutically effective amount of doxycycline
or pharmaceutically acceptable complexes, salts, polymorphs, hydrates, solvates,
enantiomers or racemates thereof wherein the composition comprises doxycycline and
hydrophobic release controlling agent(s), and optionally other pharmaceutically
acceptable excipients.
Yet another object of the present invention provides a controlled release pharmaceutical
compositions comprising therapeutically effective amount of doxycycline or
pharmaceutically acceptable complexes, salts, polymorphs, hydrates, solvates,

enantiomers or racemates thereof wherein the composition comprises doxycycline and
hydrophobic release controlling agent(s), and optionally a wicking agent.
Yet another object of the present invention provides a controlled release pharmaceutical
compositions comprising therapeutically effective amount of doxycycline or
pharmaceutically acceptable complexes, salts, polymorphs, hydrates, solvates,
enantiomers or racemates thereof wherein the composition comprises doxycycline and
hydrophobic release controlling agent(s), optionally a wicking agent and additionally
hydrophilic rate controlling components.
Yet another object of the invention provides modified release pharmaceutical
compositions comprising doxycycline or pharmaceutically acceptable complexes, salts,
polymorphs, hydrates, solvates, enantiomers or racemates thereof, comprising a core
wherein said core comprises doxycycline or pharmaceutically acceptable complexes,
salts, polymorphs, hydrates, solvates, enantiomers or racemates thereof, with one or more
auxiliary pharmaceutical excipients and a coating layer comprising rate controlling
hydrophobic and hydrophilic agent(s).
Summary of the invention
The present invention provides a modified release preparation having one or more coated
core elements, each core element including an active ingredient and having modified
release coating, which itself functions as the stabilizing layer as well as the release
modifying layer.
Modifying release preparations in the present invention will typically be such as to
provide a delayed release of the active ingredient, with reference to the active ingredients
dissolution profile. In this respect, where the modified release is such as to provide a
delayed release the preparation aims to slow the release of the active in the stomach to
minimize the side effects of the active that may caused by release of the active in the
stomach. Such side effects include nausea and GI irritation.

Our delayed release preparations aim for the drug to be released in the upper regions of
the small intestine, for a number of reasons, as follows: the drug should be able to start
working as soon as possible after ingestion without side effects caused by drug being
released in the stomach; the conditions in the small intestine are usually optimum for
drug absorption; and to avoid acid degradation of the drug in the stomach. Therefore
there would be release of a drug after a lag period, if the residence time is longer or the
stomach conditions are different from usual, but the release preparation, so the high-
localized concentrations that cause nausea and irritation do not occur.
An important aspect of the manufacture (and also the regulatory review and approval) of
all modified release preparations, including delayed release preparations, concerns their
stability over extended periods of time, particularly their ability to provide a in-vitro
dissolution profile that is largely unaffected during the intended shelf life of their
preparation.
In this respect, it has been found that the dissolution profile for a modified release
preparations in accordance with the present invention is significantly less affected after
being subjected to storage. This gives rise to a high degree of confidence, when
determining an expiration date. It also permits an extended expiration date to be set.
Rationale for developing a single coat for formulation
The present invention provides a stable modified release preparation having one coated
layer, preferably a single coated modified release formulation, here in this formulation
the single coat itself functions as stabilizing coat as well as modified release coat so that,
upon dissolution testing, the difference in cumulative amount of active ingredient
released at post storage and pre-storage is within 30 percent, preferably within 20
percent, preferably 10 percent at majority of time points.
The modified release coating may contain between 40 to 90% w/w enteric polymer, and
between 10 to 60% w/w water-soluble or/and water permeable material, based on the
total weight of the modified release coating. The modified release coating may also

contain 0 to 30% w/w of a plasticizer, based on the total weight of the modified release
coating. The polymer coat weight of the modified release coating (as a percentage of the
total pellet) will vary depending on the delay desired and the polymer used, but generally
will be between and 5%w/w and 20%w/w. By polymer coat weight is meant the polymer
and plasticiser in the coating layer, and does not include additives such as talc, which do
not significantly affect the release rate of the pellet.
The stabilizing coat or the modified release coating may be applied to a core element in
any suitable manner such as by fluidised bed coating, including wurster coating, and rota
coating.
In a preferred form, both coats will be applied by wurster coating.
Drying the pellet using any one of a number of drying techniques known in the art, such
as oven drying or drying in a fluidised bed apparatus, may further improve stability.
Enteric coating: The term "enteric coating" as used herein relates to a mixture of
pharmaceutically acceptable excipients, which is applied to the pellets to protect the
pellets during the digestive process. The enteric coating may be applied through an
aqueous dispersion or after dissolving in appropriate solvent. Specific enteric coatings
may be selected based on any combination of the following criteria:
1. Resistance to dissolution and disintegration in the stomach
2. Impermeability to gastric fluids and drug/carrier/enzyme while in the stomach
3. Ability to dissolve or disintegrate rapidly at the target intestine site.
4. Physical and chemical stability during storage
5. Non-toxicity
6. Easy application as a coating (substrate friendly); and
7. Economical practicality
Examples of enteric coating material are not limited to anionic carboxylic polymers
exhibiting pH-dependent solubility profile, shellac, acrylic polymers and copolymers of
methacrylic acid, Eudragit series E, L, S, RL, RS and NE (Rohm Pharma) are available as
solubilized in organic solvent, aqueous dispersion, or dry powders. The Eudragit series

RL, NE and RS are insoluble in the gastrointestinal tract but are permeable and are used
primarily for extended release.
Detailed description of the Invention
The dosage forms of the present invention typically contain 25 to 200 mg doxycycline as
base. The dosage forms of the invention optionally may comprise pharmaceutically
acceptable complexes, salts, polymorphs, hydrates, solvates, enantiomers or racemates of
doxycycline.
"Pharmaceutical composition" refers to the combination of one or more drug substances
and one or more excipients.
"Drug product," "pharmaceutical dosage form," "dosage form," "final dosage form" and
the like, refer to a pharmaceutical composition that is administered to a subject in need of
treatment and generally may be in the form of tablets, micro tablets, tablet filled in
capsule, micro tablets filled in capsule, capsules, sachets containing powder or granules,
pellets, liquid solutions or suspensions, patches, and the like.
The term "controlled release compositions" herein refers to any composition or dosage
form which comprises an active drug and which is formulated to provide a longer
duration of pharmacological response after administration of the dosage form than is
ordinarily experienced after administration of a corresponding immediate release
composition comprising the same drug in the same amount. Controlled release
compositions include, inter alia, those compositions described elsewhere as "extended
release", "delayed release", "sustained release", "prolonged release", "programmed
release", "time release" and/or "rate controlled" compositions or dosage forms.
The term "wicking agent" is defined as any material with the ability to draw water into
the network of a delivery dosage form. By so doing, a wicking agent provides enhanced
flow channels for the pharmaceutical agent, which has been made predominantly into its
solubilized form.
The hydrophobic release controlling agents are selected from but are not limited to
polyvinyl acetate dispersion, ethyl cellulose, cellulose acetate, cellulose propionate

(lower, medium or higher molecular weight), cellulose acetate propionate, cellulose
acetate butyrate, cellulose acetate phthalate, cellulose triacetate, poly (methyl
methacrylate), poly (ethyl methacrylate), poly (butyl methacrylate), poly (isobutyl
methacrylate), and poly (hexyl methacrylate), poly (isodecyl methacrylate), poly (lauryl
methacrylate), poly (phenyl methacrylate), poly (methyl acrylate), poly (isopropyl
acrylate), poly (isobutyl acrylate), poly (octadecyl acrylate), waxes such as beeswax,
carnauba wax, paraffin wax, microcrystalline wax, and. ozokerite; fatty alcohols such as
cetostearyl alcohol, stearyl alcohol, cetyl alcohol and myristyl alcohol, and fatty acid
esters such as glyceryl monostearate; glycerol monooleate, acetylated monoglycerides,
tristearin, tripalmitin, cetyl esters wax, glyceryl palmitostearate, glyceryl behenate, zein,
Eudragit L100, S100, NE30D, other varieties and hydrogenated vegetable oils or their
mixtures thereof.
The hydrophilic release controlling agents are selected from but are not limited to
hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), polyethylene
oxide, polyvinyl alcohol, polyvinylpyrrolidone, xanthan gum, guar gum, chitosan and its
derivatives, carbomer, carrageenan, carboxymethyl cellulose, sodium alginate,
polyglycolized glycerides, polyethyleneglycol, or mixture thereof.
The wicking agents are selected from the group comprising hydrophilic, organic,
polymeric, fusible substance or a particulate soluble or insoluble inorganic material.
Suitable hydrophilic, organic, fusible wicking agents include polyethylene glycols
(PEGs) of various molecular weights e.g. 1,000 to 20,000 preferably 4,000 to 10,000 and
suitable particulate inorganic wicking agents include dicalcium phosphate and lactose. It
is preferred to use a hydrophilic fusible, organic polymeric as wicking agent. Other
examples of wicking agents include high HLB surfactants (for example Tween 20,
Tween 60 or Tween 80; ethylene oxide propylene oxide block copolymers, ionic
surfactants such as sodium lauryl sulfate, sodium docusate, non- swelling hydrophilic
polymers such as cellulose ethers, complexing agents such as: polyvinyl pyrrolidone,
cyclodextrins and non- ionic surface active agents; and micelle forming agents, which
may be surface active agents such as Tweens (Poly (ethylene Oxide) modified sorbitan

monoesters), Spans (fatty acid sorbitan esters), sodium lauryl sulfate and sodium
docusate.
The term "controlled release pharmaceutical compositions" includes a pharmaceutical
composition that encompasses one or more individual units. The units may be a capsule
or tablet or may be in form of granules, pellets, minitablets or beads.
The compositions of the present invention can also include other materials such as
binders, diluents, anti-adherents, glidants and lubricants.
Diluents may be, for example, any pharmaceutically acceptable, non-toxic diluent.
Particular examples include lactose, dextrose, sucrose, maltose, microcrystalline
cellulose, starch, calcium hydrogen phosphate, mannitol and the like.
Binders may be, for example, starch, sugars, gums, low molecular weight hydroxypropyl
methylcellulose, povidone, hydroxypropyl cellulose, hydroxyethyl cellulose or the like.
Lubricants may be, for example, talc, magnesium stearate, calcium stearate, stearic acid,
sodium stearyl fumarate, sodium benzoate or the like.
Antiadherents and Glidants may be, for example, colloidal silicon dioxide, talc or the
like.
Solid oral dosage forms of the present invention may be prepared by any conventional
techniques for example dry granulation, direct compression, wet granulation, melt
granulation and extrusion-spheronization.
The following examples are intended to be illustrative and non-limiting:

PROCEDURE:
Preparation of core pellets
Step-I Shift Doxycycline Hyclate, Microcrystalline cellulose, Lactose monohydrate and
Sodium lauryl sulfate through 40#(420 screen) and mix properly for 10-15 min.
Step-I Prepare binder solution of sodium chloride by dissolving it in required qty of
water.
Step-III Granulate blend of Step-I with Binder solution prepared in Step-II
Step-IV Granules were extruded in a screw feeder model extruder by using lmm screen
Step-v Above prepared extrudate was spheronised in a Spheroniser for 30 sec.
Step-VI Pellets formed from above step were dried in a rapid dryer for l-2hr at temp-
55°C
Step-VII Dried pellets were screened through 16# passed and 35# retained mesh.
Coating of pellets
Step-VIII coating solution was prepared by dissolving HPMCP-55 and HPMC-3cps in
isopropyl alcohol and Dichloro methane Mixture.

Step-IX Coating solution prepared above was sprayed upon Pellets taken in Fludised bed
processor (pam glat GPCG1.1) coated pellets were cured for 30 min in processor.
Step-X Pellets were given for Assay.
Preparation of tablets
Step-XI Lactose anhydrous-DCL-21and Required Wt of pellets were mixed together in a
double cone blender for 10 min at 10 rpm.
Step-XII Above prepared blend was mixed with cross caramellose sodium and mixed for
5min.then blend was lubricated using magnesium stearate for l-2min.
Step-XIV finally above blend was compressed using 19.8*9.5mm oval shaped punch.


We claim:
1. A stable modified release preparation having single coated core elements, each core
element comprising an active ingredient selected from the group consisting of the acid
salts of doxycycline, trospium, tetracycline, oxytetracycline, minocycline,
chlortetracycline or demeclocycline and having a modified release coating.
2. The preparation according to claim 1, wherein the difference in cumulative amount of
active ingredient released at the majority of time points on the post-storage dissolution
profile and on the pre-storage dissolution profile is within 30 percent.
3. The preparation according to claim 1, wherein the difference in cumulative amount of
active ingredient released at the majority of time points on the post-storage dissolution
profile and on the pre-storage dissolution profile is preferably within 20 percent.
4. The preparation according to claim 1, wherein the difference in cumulative amount of
active ingredient released at the majority of time points on the post-storage dissolution
profile and on the pre-storage dissolution profile is preferably within 10 percent.
5. The preparation according to claim 1, wherein the modified release coating is a
delayed release coating.

8. The preparation according to claim 1, wherein the modified release coating is an
enteric coating, a semi-enteric coating, a delayed release coating, a pulsed release
coating, a mixture of enteric polymers, or a mixture of an enteric polymer with a water
permeable, water swellable or water soluble polymer material.
9. The preparation according to claim 8, wherein the water soluble or water permeable
materials are one or a mixture of hydroxypropylmethyl cellulose, hydroxypropyl
cellulose, polyvinyl pyrrolidone and polyethylene glycol.

10. The preparation according to claim 1, wherein the modified release coating comprises
one or more of hydroxypropylmethyl cellulose phthalate, a pH dependent anionic
methacrylate based polymer, or hydroxypropylmethyl cellulose acetate succinate.
11. A method of administering an active ingredient that, upon administration in an
immediate release form, normally causes nausea and gastric irritation, the method
comprising administering a modified release preparation in accordance with claim 1.
12. The preparation according to claim 1, the preparation being provided as a plurality of
coated core elements in a capsule.
13. The preparation according to claim 1, the preparation being provided as a plurality of
coated core elements compressed to form a tablet.
14. The preparation according to claim 13, wherein the percentage of coated core
elements in each tablet is in the range of 20 to 40 by weight of the total dosage weight.
18. The preparation according to claim 13, wherein the percentage of coated core
elements in each tablet is in the range of 25 to 35% by weight of the total dosage weight.
19. The preparation according to claim 13, wherein the percentage of coated core
elements in each tablet is about 30% by weight of the total dosage weight.
20. The preparation according to claim 1, wherein the modified release coating is a
delayed release coating, the active ingredient is an acid salt of doxycycline, and the
preparation is provided as a plurality of coated core elements compressed to form a
tablet.

21. A tablet for oral administration, the tablet being a modified release preparation having
single coated core elements, each core element comprising an active ingredient
comprising an acid salt of doxycycline and having a modified release coating.
22. The preparation according to claim 21, wherein the difference in cumulative amount
of active ingredient released at the majority of time points on the post-storage dissolution
profile and on the pre-storage dissolution profile is within 30 percent.
23. A pellet for use in a dosage form for oral administration, the pellet being a modified
release preparation having single coated core elements, each core element comprising an
active ingredient comprising an acid salt of doxycycline and having a modified release
coating.
24. The preparation according to claim 23, wherein the difference in cumulative amount
of active ingredient released at the majority of time points on the post-storage dissolution
profile and on the pre-storage dissolution profile is within 30 percent.
25. The method according to claim 14, wherein the modified release coating is a delayed
release coating, and the active ingredient is an acid salt of doxycycline.
26. A stable single coated doxycycline composition comprising atleast one enteric-coated
polymer and one non-enteric coated polymer without intermediate layer.

A stable modified release preparation having single coated core elements, each core
element comprising an active ingredient selected from the group consisting of the acid
salts of doxycycline, trospium, tetracycline, oxytetracycline, minocycline, chlortetracycline or demeclocycline and having a modified release coating. . A pellet for use in a dosage form for oral administration, the pellet being a modified release preparation having single coated core elements, each core element comprising an active
ingredient comprising an acid salt of doxycycline and having a modified release coating. A stable single coated doxycycline composition comprising at least one enteric-coated polymer and one non-enteric coated polymer without intermediate layer