FORM-2
THE PATENTS ACT, 1970
(39 of 1970)
COMPLETE
Specification
(Section 10; rule 13)
PROCESS FOR MAKING PHARMACEUTICAL COMPOSITIONS
EMCURE PHARMACEUTICALS LTD.
of Emcure House, T-184, M.I.D.C., Bhosari,
Pune 411 026, Maharashtra, India,
an Indian Company
7 - 7 - 2 0 0 4
THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE NATURE OF THIS INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED:-


This invention relates to a pharmaceutical composition containing doxycycline and ambroxol as the active ingredients.
In antimicrobial therapy, a continuous battle exists between the adaptation capability of microorganisms (development of resistance) and the preparation of novel drugs.
Tetracycline is a long-known antimicrobial substance. Out of its derivatives, doxycycline has a very favorable bacteriostatic effect on a wide range of gram-positive pathogens and a moderate effect on gram-negative microorganisms. It acts by inhibiting protein synthesis by binding to 30S ribosome in susceptible organisms. Doxycycline has a place in the management of chronic bronchitis and sinusitis. Doxycycline has the advantage of requiring only single daily dosing unlike other tetracyclines.
Doxycycline is more active than tetracycline against many species including enterococci and various anaerobes. Cross-- resistance is common although some tetracycline-resistant staphylococcus aureus respond to doxycycline. MICs for most sensitive organisms range from 0.1-2 mcg./ml.
Doxycycline is readily and almost completely absorbed from the gastro intestinal tract and absorption is not significantly affected by food. Mean peak plasma concentrations of 2.6

mcg/ml have been reported after 200 mg dose by mouth falling to 1.45 mcg/ml at 24 hours. About 80-95% of doxycycline in circulation is reported to be bound to plasma proteins. Its biological half life varies from 12-24 hours. Doxycycline is more liquid soluble than tetracyclines. It is widely distributed in body tissues and fluids. In patients with normal renal function about 40% of a dose is slowly excreted in the urine. The majority of the dose of Doxycycline is excreted in the faeces following chelation in the intestines. The kinetics of Doxycycline has been reportedly altered on patients receiving drugs, which induce hepatic metabolism. Doxycycline is not started to accumulate significantly in patients with renal impairment although excretion in urine is reduced.
Although sputum concentrations of doxycycline are low, the drug is beneficial in patients with all kinds of bronchitis.
Presence of thick sputum in bronchitis pose problems not only in achieving high concentration of the antibiotic, but also in breathing. This makes the patient cough repeatedly. In such situations, it wold be idea to make the sputum thin, less viscid and decrease its stickiness.
Ambroxol, 4-[[(2-amino-3,5-dibromophenyl) methyl] amino] cyclohexanol or N-(trans-p-hydroxycylohexyl) - (2-ammo-3,5-dibromobenzyl)amine, is a known compound.

Ambroxol hydrochloride too is known to this art, as is the pharmaceutical activity thereof. Ambroxol is a mucolytic agent used in the treatment of respiratory disorders associated with viscid or excessive mucus. Ambroxol is a metabolite of Bromhexine. It has a mucolytic and mucokinetic activity. It depolymerizes mucopolysaccharides directly and liberates lysosomal enzymes.
Ambroxol HC1 , is a safe and effective expectorant. Nonetheless, it possesses a relatively short biological half-life and, therefore, it typically must be administered at least three times and typically five times a day in order to elicit its full activity.
Thus, need continues to exist in this art for an improved dosage form of ambroxol HC1 that will permit a decrease in the number of administrations, to not only reduce the burden on the patient but also to increase his compliance, thus providing greater therapeutic benefits.
Ambroxol is a mucolytic agent. It has the property of stimulating—and enhancing the surfactant synthesis accompanied by alveolar macrophage activation. Surfactant activity can reduce the surface tension of the sputum, thereby making it less sticky. It also stimulates the bronchial ciliary movement. Thereby facilitating the expulsion of mucous. Clinical studies, where Ambroxol and antibiotics were given

together it was found that Ambroxol helps in increasing the volume of sputum by decreasing the sputum thickness, there by giving more favourable clinical evolution. Macrolides like Erythromycin level in broncho pulmonary tissue following oral administration in rats, when compared with those who received the same treatment and additionally also when compared with those who received the same treatment and additionally also receiving ambroxol showed that addition of ambroxol was correlated with an increase of 27% of antibiotic in these tissues. The authors concluded that ambroxol can increase the antibiotic penetration in the lungs.
Similarly, in clinical samples of alveolar lavage fluids and lung tissues antibiotic levels were found to be higher in those patients who were treated with both antibiotics and Ambroxol than those who received only antibiotics.
According to this invention there is provided a process for manufacturing a composite tablet consisting of Doxycycline and ambroxol as active ingredients comprising the steps of making an ambroxol core by mixing together particulate ambroxol with a filler such as lactose a programmed release agent to form a first mixture; adding a wetting agent with a binder to the first mixture to form a wet mass; granulating the wet mass and sieving it to obtain particles at least less than 30 mesh; drying the granulated wet mass till the moisture content reaches below 2% to obtain dry core mass,

sieving the dry core mass to obtain granules less than 20 mesh and lubricating the granules with a lubricant to obtain lubricated core granules; making a doxycycline shell
by mixing together particulate doxycycline with a flow enhancing agent and adding a wetting agent to form a wet mass; granulating the wet mass and sieving the granulated mass to obtain granules of less than 30 mesh; dry the granules between 40 to 60 degrees celsius to obtain granules having moisture content of less than 2%; sieving the dry granules to obtain active granules of less than 20 mesh, mix the dry active granules with dry filler particles, glidant particles and a disintegrant of size less than 50 mesh to obtain shell mixture and lubricating the shell mixture with a lubricant to obtain lubricated doxycycline shell mixture; forming an ambroxol core by transferring the lubricated core granules to a first compression die and compressing the lubricated core granules into a soft ambroxol core at pressures ranging from 1 to 2kg/sq cm; providing the ambroxol core with a doxycycline shell by transferring the soft ambroxol core to a second compression die, introducing the lubricated doxycycline shell mixture to surround the ambroxol soft core and compressing the doxycycline shell mixture around the soft ambroxol core at compression pressures ranging from 7 to 20 kg sq cm to form an ambroxol core doxycycline shell tablet; and film coating the said tablet with a polymeric film. The invention

will now be described with reference to the accompanying examples :
Example 1 : A tablet was prepared using the following
ingredients:
Each modified sustained release tablet contains:
Ambroxol Hydrochloride [BP] - 75.0 mg.
Doxycycline monohydrate [USP] equivalent
to Doxycycline anhydrous - 100.0 mg.

Colour : Yellow oxide of Iron & Titanium dioxide CORE:


Sodium lauryl sulphate IP - 2.0 mg
Sodium starch glycolate IP - 12.0 mg
Povidone IP - 8.0 mg
Colloidal silicon Dioxide IP - 4.0 mg
Purified Talc IP - 1.0
Magnesium stearate IP - 3.0 mg
Total weight of Shell 330.0mg
Contains 2% overages of Doxycycline monohydrate
Total compression weight of tablet - 520.0 mg
Procedure:
Core:
Sift Ambwxol, HPMC K4M, and HPMC K100M through 60
mesh sieve - stage 1
Sift Lactose through 40 mesh sieve — stage 2
Mix stage 1 with stage 2 - stage 3.
Dissolve Povidone (PVPK-30) in purified Water 40 gm. -
stage 4
Mix stage 3 - with stage 4 and granulate - stage 5 .
Pass stage 5 through 12 mesh
Dry it for sufficient period of time till Loss on drying reaches
to 1.4%.
Sift the above dried material through 16 mesh sieve - stage 6
Sift magnesium stearate through 60 mesh sieve & lubricate
Stage 6 to get stage 7.
Shell :
Pass through 40 mesh Doxycycline, microcrystalline
cellulose and mix well stage 1.

Dissolve first sodium lauryl sulphate in 90 gm. IPA & add
Povidone in it stage 2.
Granulate stage 1 by stage 2 and pass the wet mass through
mesh 12.
Dry the granulated material at 45°C - 50°C LOD + 1.74% &
then pass through 16 mesh ~ stage 3.
Sift Colloidal Silicon Dioxide & Sodium starch glycolate &
talc through 40 mesh ~ stage 4.
Add stage 4 to stage 3
Pass magnesium stearate through 60 mesh & lubricate the
granulated material - stage 5.
Compression:
Feed core & shell granules into two separate hoppers of drycoata machine. The granules of core tablets were fed to the die cavity and a soft tablet is compressed at a pressure of 1.2 kg/sq cm. The soft core tablet is transferred mechanically to the second die cavity wherein the granules of shell were also fed. The total tablet was thus compressed on the second die cavity turret at a pressure of 10 kg/sq cm.
The tablets compressed in such a way were loaded in coating pan which were rotated at 8 rpm. The coating solution was made using:
Hydroxy propyl Methyl cellulose (5 cps) IP
Propylene glycol 6000 IP (1.0% W\W)
Purified Talc IP (1.0% W\W)

Titanium dioxide IP (0.6% W\W)
Iron oxide yellow IP (0.04% W\W)
Methylene Chloride (49.66% W\W)
Isopropyl alcohol (44.00% W\W)
This solution was sprayed under drying to form a continuous smooth Film on the tablets to form a film coated ambroxol core doxycycline shell film coated tablet.
Example 2 : A tablet was prepared using the following
ingredients:
Each modified sustained release tablet contains:
Ambroxol Hydrochloride [BP] - 75.0 mg.
Doxycycline hyclate [USP] equivalent
to Doxycycline anhydrous - 115.411 mg.

Colour : Yellow oxide of Iron & Titanium dioxide
CORE:
Ambroxol HCI - 77.25 mg.
Lactose (?) IP - 48.75 mg.
HPMC K4M IP - 40.0 mg.
HPMC K100M IP - 12.0 mg.
Povidone IP - 10.0 mg.
Magnesium stearate IP - - 2.0 mg.
Purified water IP -
Total weight of Core 190.0 mg.

Contains 3% overages of Ambroxol HCI
Shell:
Doxycycline hyclate [USP] - 114.411 mg
Equivalent to Doxycycline anhydrous
Monocrystalline cellulose
(Ambicel Ph l02) IP - 184.29 mg
Sodium lauryl sulphate IP - 2.0 mg
Sodium starch glycolate IP - 12.0 mg
Povidone IP - 8.0 mg
Colloidal silicon Dioxide IP - 4.0 mg
Purified Talc IP - 1.0
Magnesium stearate IP - 3.0 mg
Total weight of Shell 330.0mg
Contains 2% overages of Doxycycline hyclate
Total compression weight of tablet - 520.0 mg
Procedure:
Core :
Sift Ambroxol, HPMC K4M, HPMC K100M through 60
mesh sieve — stage 1
Sift Lactose through 40 mesh sieve — stage 2
Mix stage 1 with stage 2 - stage 3.
Dissolve Povidone- (PVPK-3D) in purified Water 40 gm. -
stage 4
Mix stage 3 - with stage 4 and granulate - stage 5 .
Pass stage 5 through 12 mesh
Dry it for sufficient period of time till Loss on drying reaches
to 1.4%.

Sift the above dried material through 16 mesh sieve - stage 6
Sift magnesium stearate through 60 mesh sieve & lubricate
Stage 6 to get stage 7.
Shell :
Pass through 40 mesh Doxycycline, microcrystalline
cellulose and mix well stage 1.
Dissolve first sodium lauryl sulphate in 90 gm. IPA & add
Povidone in it stage 2.
Granulate stage 1 by stage 2 and pass the wet mass through
mesh 12.
Dry the granulated material at 45°C - 50°C LOD + 1.74% &
then pass through 16 mesh — stage 3.
Sift Colloidal Silicon Dioxide & Sodium starch glycolate &
talc through 40 mesh - stage 4.
Add stage 4 to stage 3
Pass magnesium stearate through 60 mesh & lubricate the
granulated material - stage 5.
Compression:
Feed core & shell granules into two separate hoppers of drycoata machine. The granules of core tablets were fed to the die cavity and a soft tablet is compressed at a pressure of 1.2 kg/sq cm. The soft core tablet is transferred mechanically to the second die cavity wherein the granules of shell were also fed. The total tablet was thus compressed on the second die cavity turret at a pressure of 10 kg/sq cm.

The tablets compressed in such a way were loaded in coating
pan which were rotated at 8 rpm. The coating solution was
made using:
Hydroxy propyl Methyl cellulose (5 cps) IP

Propylene glycol 6000 IP (1.0% W\W)
Purified Talc IP (1.0% W\W)
Titanium dioxide IP (0.6% W\W)
Iron oxide yellow IP (0.04% W\W)
Methylene Chloride (49.66% W\W)
Isopropyl alcohol (44.00% W\W)
This solution which had a viscosity of 25 cps was sprayed under drying to form a continuous smooth Film on the tablets to-form a film coated ambroxol core doxycycline shell film coated tablet. The testing of the tablets revealed that there was improvement in the tissue/serum antibiotic levels
there was improvement in the remission of cough and changes in chest pathological signs.
The normal dose of Ambroxol is 30 mg 5 timed a day. This normal dosage_causes inconvenience to the patient because being a mucolytic, ambroxol causes copious sputum formation. The 75 mg of ambroxol twice daily introduced in accordance with this invention-controls the symptoms for full 24 hours and the above dose is well tolerated. It was also found that the high dose of Ambroxol such as 500 - mg b.d.

given for 5 days to healthy volunteers were well tolerated. No severe adverse events were reported and no drug-induced changes in the clinical laboratory values were observed indicating that the drug is safe upto this high dosage.
Long term clinical studies with Ambroxol 75 mg/day o.d. upto 6 months 5,635 patients supports this point and was found to be well tolerated and effective in prevention of chronic bronchitic exacerbation.
These features make 75 mg of Ambroxol, an optimal dose to be combined with doxycycline an antibiotic whose dosage schedule is twice daily and has an important role in respiratory tract infections. The optimum dose of Doxycycline is 100 mg once daily. Therefore, the tablet in accordance with this invention combines optimal doses of both the drugs.
Anecdotal data
Case 1 : A 20 year old boy was suffering from bronchitis & subsequent congestion. He was given antibiotics and tablets of Ambroxol 30 mg but the symptoms persisted. When given the combination tablet in tablet form in accordance with this invention , due to the sustained release action of ambroxol combined with antibiotic action of Doxycycline, the

symptoms of congestion were relieved much faster. The patient experienced clear throat and ease of breathing.
Case 2: A 55 year old lady was suffering from bronchitis & pulmonary infection. She was given antibiotics and tablets of Ambroxol 30 mg but due to frequent administration of ambroxol copious mucous secretions were experienced which caused discomfort for the patient. When given the combination tablet in tablet form, due to the sustained release action of ambroxol combined with antibiotic action of Doxycycline, the symptoms of congestion were relieved much faster. Also, due to sustained release of drug in the body the frequency of administration was reduced. The patient experienced better comfort by using the combination of Doxy + ambroxol.
DISSOLUTION OF THE AMBROXOL CORE DOXYCYCLINE SHELL FILM TABLET
% RELEASE OF DOXYCYCLINE HCI:

% RELEASE OF AMBROXOL HCI:




Although the invention has been described in terms of particular
embodiments and applications, one of ordinary skill in the art, in light
of this teaching, can generate additional embodiments and
modifications without departing from the spirit of or exceeding the
scope of the claimed invention. Accordingly, it is to be understood
that the drawings and descriptions herein are proffered by way of
example to facilitate comprehension of the invention and should not
be construed to limit the scope thereof.

We Claim:
1. A process for manufacturing a composite tablet consisting of Doxycycline and ambroxol as active ingredients comprising the steps of
making an ambroxol core by mixing together particulate ambroxol with a filler such as lactose a programmed release agent to form a first mixture; adding a wetting agent with a binder to the first mixture to form a wet mass; granulating the wet mass and sieving it to obtain particles at least less than 30 mesh; drying the granulated wet mass till the moisture content reaches below 2% to obtain dry core mass, sieving the dry core mass to obtain granules less than 20 mesh and lubricating the granules with a lubricant to obtain lubricated core granules; making a doxycycline shell
by mixing together particulate doxycycline with a flow enhancing agent and adding a wetting agent to form a wet mass; granulating the wet mass and sieving the granulated mass to obtain granules of less than 30 mesh; dry the granules between 40 to 60 degrees celsius to obtain granules having moisture content of less than 2%; sieving the dry granules to obtain active granules of less than 20 mesh, mix the dry active granules with dry filler particles, glidant particles and a disintegrant of size less than 50 mesh to

obtain shell mixture and lubricating the shell mixture with a lubricant to obtain lubricated doxycycline shell mixture; forming an ambroxol core by transferring the lubricated core granules to a first compression die and compressing the lubricated core granules into a soft ambroxol core at pressures ranging from 1 to 2kg/sq cm; providing the ambroxol core with a doxycycline shell by transferring the soft ambroxol core to a second compression die, introducing the lubricated doxycycline shell mixture to surround the ambroxol soft core and compressing the doxycycline shell mixture around the soft ambroxol core at compression pressures ranging from 7 to 20 kg sq cm to form an ambroxol core doxycycline shell tablet; and film coating the said tablet with a polymeric film.
2. A process for manufacturing a composite tablet consisting of Doxycycline and ambroxol as active ingredients as claimed in claim 1, in which the ratio of doxycycline to ambroxol in the tablet is in the region of 4 : 3 allowing for over ages.
3. A process for manufacturing a composite tablet consisting of Doxycycline and ambroxol as active ingredients as claimed in claim 1, in which the programmed release agent for the ambroxol core is Hydroxy proply methyl cellulose.

4. A process for manufacturing a composite tablet consisting of Doxycycline and ambroxol as active ingredients as claimed in claim 1, in which the ratio of the core to the shell ranges between 2:3 to 1: 2.
5. A process for manufacturing a composite tablet consisting of Doxycycline and ambroxol as active ingredients as claimed in claim 1, in which the solution with which the tablet is sprayed to form a film has a viscosity ranging from 20 to 30 cps.
6. A process for manufacturing a composite tablet consisting of Doxycycline and ambroxol as active ingredients as claimed in claim 1, in which the lubricant used is magnesium stearate.
7. A process for manufacturing a composite tablet consisting of Doxycycline and ambroxol as active ingredients as described herein with reference to the accompanying examples.
Dated this 30th day of May, 2002.
Mohan Dewan Of R.K. Dewan & Co., Applicants' Patent Attorneys