DESC:FIELD OF INVENTION:
The present invention relates to pharmaceutical composition more particularly Inlay tablet pharmaceutical formulations comprising an inner core tablet of Camylofin and outer tablet of Diclofenac and pharmaceutically acceptable salts thereof. The invention also relates to processes of preparing such compositions. 5
BACKGROUND:
The existing marketed formulations of Diclofenac and Camylofin are generally available as Conventional tablets, however the process of preparing the conventional tablets formulations are not stable . Inventors of the present invention found that it was difficult to obtain the required stability through the conventional tablets due to 10 compatibility issues of drugs and drugs-excipient interactions. Diclofenac and Camylofin have different physicochemical properties, which can result in compatibility issues during formulation. Incompatibilities can lead to reduced stability, changes in drug release profiles, or even chemical degradation. It is crucial to conduct through compatibility studies to ensure that the two drugs can coexist in 15 a stable and effective formulation.
The selection of excipients used in the tablet formulation can also impact the stability, dissolution, and release of Diclofenac and Camylofin. Excipients were found to interact with the drugs, affecting their chemical integrity or altering their release
3
kinetics. Thus compatibility studies were performed to identify potential drug-excipient interactions and select appropriate excipients that maintain the desired drug properties.
Indian patent application no. 0611/MUM/2007 described the preparation of Inlay tablets of Diclofenac and misoprostol wherein misoprostol is present as an inner 5 inlayed tablet within the outer Diclofenac tablet where Diclofenac salt is present in form of coated beads.
To overcome the issues faced while formulating the fixed dose combination of Diclofenac and Camylofin or pharmaceutically acceptable salts thereof, the inventors of the present invention surprisingly found that preparation of the inlay tablets 10 wherein both drugs remain as complete separate entities solves the problems faced during the stability & safety of the of conventional tablets of the Diclofenac and Camylofin or pharmaceutically acceptable salts thereof.
SUMMARY OF THE INVENTION:
The present invention provides an alternative formulation to overcome the problems 15 associated in formulating a stable fixed dose combination of Diclofenac and Camylofin or pharmaceutically acceptable salts thereof.
4
BRIEF DESCRIPTION OF FIGURES:
FIG. 1 is a diagrammatic representative of Inlay tablet of present invention showing inner core and outer coat.
DETAILED DESCRIPTION OF INVENTION:
Those skilled in the art will be aware that the present disclosure is subject to variations 5 and modifications other than those specifically described. It is to be understood that the present disclosure includes all such variations and modifications. The disclosure also includes all such compositions, components of the composition, referred to or indicated in this specification, individually or collectively and all combinations of any or more of such components or composition. 10
Definitions
For convenience, before further description of the present disclosure, certain terms employed in the specification, and examples are collected here. These definitions should be read in the light of the remainder of the disclosure and understood as by a person of skill in the art. The terms used herein have their meanings recognized and 15 known to those of skill in the art, however, for convenience and completeness, particular terms and their meanings are set forth below.
The articles “a”, “an” and “the” are used to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article.
5
The terms “comprise” and “comprising” are used in the inclusive, open sense, meaning that additional elements may be included. It is not intended to be construed as “consists of only”.
Throughout this specification, unless the context requires otherwise the word “comprise”, and variations such as “comprises” and “comprising”, will be understood 5 to imply the inclusion of a stated element or step or group of element or steps but not the exclusion of any other element or step or group of element or steps.
The term “including” is used to mean “including but not limited to”. “Including” and “including but not limited to” are used interchangeably.
Unless defined otherwise, all technical and scientific terms used herein have the same 10 meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the disclosure, the preferred methods, and materials are now described. All publications mentioned herein are incorporated herein by reference. 15
The present disclosure is not to be limited in scope by the specific embodiments described herein, which are intended for the purposes of exemplification only. Functionally equivalent products and processes are clearly within the scope of the disclosure, as described herein.
6
The term “pharmaceutical composition” refers to delivery system in which active agents are delivered to the patients. This could be in the form of tablet, capsule, injection, liquid etc.
The term “pharmaceutically acceptable excipient” refers to inert substances other than active ingredients which are used in the preparation of pharmaceutical products. 5
The term “excipients” as used herein means a component of a pharmaceutical product that is not an active ingredient. The excipients that are useful in preparing a pharmaceutical composition are generally safe and non-toxic.
The term "inlayed tablet" as used herein refers to a tablet comprising
i) an inner core tablet 10
ii) and outer tablet compressed over the inner core tablet
iii) and wherein one surface of the inner core tablet is partially or completely exposed.
In an embodiment the inner core or outer tablet can be further coated with a coating. Various coating types known in the art can be utilized in the present invention. 15 Examples of coating types include without limitation, film coatings, enteric or pH dependent coatings, delayed release coatings, and the likes thereof.
in a preferred embodiment the inner core and outer tablet are coated with film coating.
7
An “Inlay Tablet” is a type of layered tablet in which the top surface of the core tablet instead of being completely surrounded, is completely or partially exposed. While preparation, only the bottom of the die cavity is filled with granules of the outer tablet material and core tablet is placed upon it. When compression force is applied, some outer tablet granule material is displaced to form the sides and the top surface of the 5 inner tablet remains exposed. (Figure 1)
The present invention provides a pharmaceutical composition comprising combinations of Diclofenac and Camylofin as active ingredients in a single unit dosage form wherein the composition of the present invention is an alternative of existed marketed products. The existed marketed products that are generally available in 10 market as conventional tablets comprising separate Diclofenac granules and camylofin granules. However the marketed products’ manufacturing technology is a time consuming and laborious process therefore the inventors of the present invention have developed a stable formulation which provide a single unit dosage form comprising combinations of Diclofenac and Camylofin which is stable and 15 commercially viable as compared to existing products in the market.
The present invention relates to a novel drug delivery system comprising combinations of Diclofenac and Camylofin as active ingredients in a single unit dosage form wherein the drug delivery system is meant for oral administration.
8
The present invention provides a novel composition comprising an inner core tablet having a therapeutically effective amount of camylofin or a pharmaceutically acceptable salt or enantiomer or polymorph thereof as active agents, and an outer tablet comprising therapeutically effective amount of Diclofenac or a pharmaceutically acceptable salt or enantiomer or polymorph thereof. 5
The active ingredients constituting the combination are present in the free state or in the form of one their salts, enantiomers, racemates, polymorphs, esters.
Preferred examples of salts include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, sodium salt, potassium salt, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, 10 succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.
In an embodiment Diclofenac or salts thereof is preferably Diclofenac Potassium and camylofin is Camylofin dihydrochloride.
In an embodiment the novel drug delivery system is an oral formulation comprising 15 an inner core tablet comprising Camylofin or pharmaceutically acceptable salts and an outer tablet comprising Diclofenac or pharmaceutically acceptable salts wherein the outer tablet is compressed over the inner core in such a way that top surface of the inner core is exposed.
9
In an another embodiment the present invention provides an inlay tablet formulation comprising combinations of Diclofenac potassium and Camylofin dihydrochloride as active ingredients wherein the formulation further comprises pharmaceutically acceptable excipients.
In a preferred embodiment the present invention provides inlay tablet formulation 5 comprising an inner core tablet comprising Camylofin dihydrochloride and an outer tablet comprising Diclofenac wherein the outer tablet is compressed over the inner core in such a way that top surface of the inner core is exposed.
In an embodiment the present invention provides an inlayed tablet comprising
i) an inner core tablet comprising camylofin dihydrochloride and 10 pharmaceutically acceptable excipients
ii) and outer tablet compressed over the inner core tablet, wherein the outer tablet comprises of Diclofenac potassium and pharmaceutically acceptable excipients
iii) and wherein one surface of the inner core tablet is completely or partially 15 exposed.
In an embodiment the Inlay Tablet of the present invention is a type of layered tablet in which the top surface of the core tablet instead of being completely surrounded by the outer tablet, is completely or partially exposed. While preparation, only the
10
bottom of the die cavity is filled with granules of the outer tablet material and core tablet is placed upon it. When compression force is applied, some outer tablet granule material is displaced to form the sides and the top surface of the inner tablet remains exposed. (Figure 1).
In an embodiment the amount of Diclofenac potassium present in the formulation is 5 from about 20-100 mg.
In an embodiment the amount of Camylofin dihydrochloride present in the formulation is from about 20-100 mg.
In an another embodiment the inner core tablet further comprises pharmaceutical acceptable excipients. Examples of excipients include but not limited are not limited 10 to diluent, stabilizer, disintegrant, anti-adherant , binder, glidant, lubricant or anti-capping agent, coating agents, solvents and combinations thereof.
In an another embodiment an inner core tablet comprises:
i. 30-40 wt.% camylofin dihydrochloride as an active ingredient based on uncoated weight of inner core tablet and; 15
ii. 35-40 wt.% one or more diluent based on uncoated weight of inner core tablet and;
iii. 2-6 wt.% one or more disintegrant based on uncoated weight of inner core tablet and;
11
iv. 1-5 wt.% one or more anti-adherent based on uncoated weight of inner core tablet and;
v. 1-5 wt.% one or more glidant based on uncoated weight of inner core tablet and;
vi. 2-6 wt.% one or more lubricant based on uncoated weight of inner core tablet. 5
In an another embodiment an inlay tablet comprises an inner core tablet further comprises:
vii. 39.62 wt.% camylofin dihydrochloride as an active ingredient based on uncoated weight of inner core tablet and;
viii. 44.15 wt.% microcrystalline cellulose as diluent based on uncoated weight of 10 inner core tablet and;
ix. 5.30 wt.% crospovidone and 3.78 wt.% croscarmellose sodium as disintegrant based on uncoated weight of inner core tablet and;
x. 1.50 wt.% colloidal silicon dioxide as anti-adherent based on uncoated weight of inner core tablet and; 15
xi. 1.50 wt.% talcum as glidant based on uncoated weight of inner core tablet and;
12
4.15 wt.% magnesium stearate as lubricant based on uncoated weight of inner core tablet In a preferable embodiment the inner core tablet comprises of
i) premix material comprising Camylofin dihydrochloride as the active ingredient and Microcrystalline cellulose as diluent, Crospovidone and Croscarmallose sodium as disintegrants, colloidal silicon dioxide as anti 5 adherent , talcum as glidant and magnesium sterate as lubricant,
ii) Seal coating comprising Instamoist shield (IC-MS-2398) as the coating agent and isopropyl alcohol and methylene chloride as solvent.
iii) Film coating comprising instacoat T2F (A17D20156) Green as coating agent and isopropyl alcohol ad methylene chloride as solvents. 10
In an embodiment the present invention provides process of preparing inner core tablet comprising following steps:
i. Mixing Camylofin with diluent, one or more disintegrant, anti-adherent, glidant and lubricant by dry mixing or blending in a blender.
ii. The premix was lubricated with lubricant and blended for few minutes. 15
iii. The mixture was then compressed with compressing machine. The compressed tablet was further coated with seal coating and film coating material.
13
In an embodiment an inlay tablet formulation comprises an outer tablet further comprising:
i. 10-15 wt.% Diclofenac potassium as an active ingredient based on uncoated weight of outer tablet and;
ii. 40-45 wt.% one or more diluent based on uncoated weight of outer tablet and; 5
iii. 2-6 wt.% one or more disintegrant based on uncoated weight of outer tablet and;
iv. 25-30 wt.% one or more diluent based on uncoated weight of outer tablet and;
v. 0.2-2 wt.% one or more anti-adherent based on uncoated weight of outer tablet and 10
vi. 0.2-2 wt.% one or more glidant based on uncoated weight of outer tablet and
vii. 1-5 wt.% one or more lubricant based on uncoated weight of outer tablet
In an another embodiment an inlay tablet formulation comprises an outer tablet further comprises:
i. 14.28 wt.% Diclofenac potassium as an active ingredient based on uncoated 15 weight of outer tablet and;
ii. 42.42 wt.% microcrystalline cellulose as diluent based on uncoated weight of outer tablet and;
iii. 5.72 wt.% sodium starch glycolate and 2.85 wt.% crospovidone as disintegrant based on uncoated weight of outer tablet and; 20
14
iv. 28 wt.% Pregelatinised starch as diluent based on uncoated weight of outer tablet and;
v. 0.57 wt.% colloidal silicon dioxide as anti-adherent based on uncoated weight of outer tablet and
vi. 0.30 wt.% talcum as glidant based on uncoated weight of outer tablet and; 5
vii. 1.14 wt.% magnesium stearate as lubricant based on uncoated weight of outer tablet
In an embodiment the outer tablet may further comprise additional excipient such as binders, diluents, disintegrants, lubricants, anti-adherent and solvents. In a preferred embodiment the outer tablets comprise of 10
i) Premix materials comprising Diclofenac potassium as the active agents and microcrystalline cellulose and pregelatinised starch as diluent, sodium starch glycolate/crospovidone/croscarmellose sodium as disintegrant
ii) Binding solution comprising Polyvinylpyrrolidone/starch/Hydroxypropyl cellulose as binding agent and isopropyl alcohol/Purified water as solvent. 15
iii) Lubrication material comprising Sodium starch glycolate and or crospovidone/croscarmellose sodium/ Polacrilin potassium as disintegrant, colloidal silicon dioxide as anti-adherent, talcum as glidant and magnesium stearate as lubricant.
15
In an embodiment the compressed inlay tablet further comprises of seal coat and film coat, wherein the seal coat comprises of Instamoist shield (IC-MS-2398) as coating agent and the film coat comprises of instacoat T2F (A17D20156) as coating agent.
In another embodiment the seal coated and film coated inlay tablet is further polished coating comprising stearic acid/carnauba wax as the coating agent. 5
In an embodiment the present invention provides a process of preparing outer tablet comprises following steps:
i. Sift binder and diclofenac potassium separately through a sieve with help of vibro sifter and
ii. Mix diluent and disintegrant and sift through sieve and; 10
iii. Prepare binder solution with contionous stirring to obtain clear solution and;
iv. Mix pre-sifted Diclofenac potassium, disintegrant and diluent in rapid mixer granulator and;
v. Mix binder solution to rapid mix granulator for few minutes to obtain wet granules and; 15
vi. Dry the wet granules in FBD bowl and air dry in FBD for 10 minutes and;
vii. Lubricate the dry granules by mixing disintegrant, anti-adherent, disintegrant, glidant to obtain outer tablet granules.
16
In an another embodiment outer tablet granules were filled into die cavity then inner tablet was placed over the granules and compressed to form inlay tablet. The inlay tablet was further coated with suitable coating materials.
In an embodiment the tablets of the present composition can be present as tablet in capsule composition. 5
In an embodiment the inlay tablet of the present invention can be used in treatment of abdominal pain and cramp.
Examples
The following non-limiting examples are provided to further illustrate the present invention. 10
Example 1 – Formulation details of Inlay tablets comprising Diclofenac potassium and Camylofin dihydrochloride. S. No. Ingredients Function Qty/tablet in mg
Part 1: Diclofenac Potassium Part
PREMIX MATERIALS
1
Diclofenac Potassium
Active
50
2
Microcrystalline Cellulose
Diluent
148.5
3
Sodium Starch Glycolate(S.S.G)
Disintegrant
20
4
Pregelatinised Starch USPNF (1500)
Diluent
98
BINDER MATERIALS
5
Hydroxy Propyl Cellulose
Binder
6
6
Isopropyl Alcohol (IPA)
Vehicle
160
17
LUBRICATION MATERIALS:
7
Sodium Starch Glycolate (S.S.G)
Disintegrant
10.5
8
Crospovidone XL10
Disintegrant
10
9
Colloidal Silicon Dioxide
Anti-Adherent
2
10
Talcum
Glidant
1
11
Magnesium Stearate
Lubricant
4
Average weight of uncoated tablet
350
Part:2 Camylofin Part
PREMIX MATERIALS
12
Camylofin Dihydrochloride
Active
52.5
13
Microcrystalline Cellulose
Diluent
58.5
14
Crospovidone
Disintegrant
7
15
Croscarmellose Sodium
Disintegrant
5
16
Colloidal Silicon Dioxide
Anti-Adherent
2
17
Talcum
Glidant
2
18
Magnesium Stearate
Lubricant
5.5
Average weight of uncoated tablet
132.5
SEAL COATING MATERIALS:
13
Instamoist Shield (IC-MS-2398)
Coating agent
1.5
14
Isopropyl alcohol
Solvent
12
15
Methylene chloride
Solvent
18
Average weight of Seal coated tablet
134
FILM COATING MATERIALS:
16
Instacoat T2F (A17D20156) Green
Coating agent
2
17
Isopropyl alcohol
Solvent
12
18
Methylene chloride
Solvent
18
Average weight of film coated tablet
136
Compression of Inlay-Tablet: Diclofenac Part (Lubricated Blend) + Camylofin Film Coated Tablet (Diclofenac Part: 350 mg + Camylofin tablet: 136 mg)
Total weight of Compressed Inlay Tablet: 350 mg + 136 mg: 486 mg/tablet
Coating of Inlay Tablet
Seal Coating of Inlay Tablet
19
Instamoist Shield (IC-MS-2398)
Coating agent
4
20
Isopropyl Alcohol (IPA)
Solvent
27.5
18
21
Methylene Dichloride (MDC)
Solvent
41
Actual weight of Seal coated tablets
490
Film coating of Inlay Tablet
23
Instacoat T2F (A17D20156) Green
Coating agent
12.7
24
Isopropyl Alcohol (IPA)
Solvent
102
25
Methylene Dichloride (MDC)
Solvent
158
Actual weight of Seal coated tablets
502.7
Polishing of Inlay Tablet: Coating Materials (Polishing)
26
Stearic Acid
Coating agent
0.3
27
IPA
Solvent
5
28
MDC
Solvent
5
Actual weight of Film coated tablets after Polishing
503
Example 2- % Formula of Inlay tablets comprising Diclofenac potassium and Camylofin dihydrochloride S. No. Ingredients Function %
Part 1: Diclofenac Potassium Part
PREMIX MATERIALS
1
Diclofenac Potassium
Active
14.28
2
Microcrystalline Cellulose
Diluent
42.42
3
Sodium Starch Glycolate(S.S.G)
Disintegrant
5.72
4
Pregelatinised Starch USPNF (1500)
Diluent
28
BINDER MATERIALS
5
Hydroxy Propyl Cellulose
Binder
1.72
6
Isopropyl Alcohol (IPA)
Vehicle
LUBRICATION MATERIALS:
7
Sodium Starch Glycolate (S.S.G)
Disintegrant
3
8
Crospovidone XL10
Disintegrant
2.85
9
Colloidal Silicon Dioxide
Anti-Adherent
0.57
19
10
Talcum
Glidant
0.30
11
Magnesium Stearate
Lubricant
1.14
Average weight of uncoated tablet
100
Part:2 Camylofin Part
PREMIX MATERIALS
12
Camylofin Dihydrochloride
Active
39.62
13
Microcrystalline Cellulose
Diluent
44.15
14
Crospovidone
Disintegrant
5.30
15
Croscarmellose Sodium
Disintegrant
3.78
16
Colloidal Silicon Dioxide
Anti-Adherent
1.50
17
Talcum
Glidant
1.50
18
Magnesium Stearate
Lubricant
4.15
Average weight of uncoated tablet
100
Example 3- Process of preparation
Preparation of Camylofin Inner core tablet-
Dispense the raw material as per the required quantity and then sift the dispensed material through sieve the required mesh size. 5
Prepare a premix, of camylofin 52.50 mg, Microcrystalline 58.50mg, crospovidone 7mg, croscarmellose sodium 5mg, colloidal silicon dioxide 2mg, talcum 2mg, magnesium sterate, by dry mixing or by blending in an octagonal blender at slow speed of impeller for 10minutes. Then add the magnesium sterate to the premix and blend for 3 minutes. The mixture is then compressed in a compressing machine. The 10 compressed tablet is then de-dusted and inspected for any foreign materials besides other defects.
20
Seal coat is then applied to the dedusted compressed tablets. The seal coatis prepared by taking dispensed quantities of isopropyl alcohol is an SS container and slowly add dispensed quantity of dispensed instamosit shield (IC-MS-2398) into it with continuous stirring for 10minutes. Now add dispensed quantity of methylene chloride with continuous stirring and allow it to stir for another 25minutes. Filter the solution 5 through nylon cloth and collect in SS container.
Film coat is then applied to the seal coated tablet. The film coat is prepared by taking dispensed quantity of isopropyl alcohol in SS container and slowly adding the dispensed quantity of instacoat T2F (A17D20156) green into it with continuous stirring. Allow it to stir for 10 minutes. Now add dispensed quantity of Methylene 10 chloride with continuous stirring. Allow it to stir for 25 minutes. Filter the solution through nylon cloth (200#mesh) and collect in SS container.
Process for seal and film coating- Load the core tablet in a coating pan. Pre-warm the core tablets till the product temperature reaches 30°C to 40°C for 10minutes. Take 50 pre-warmed tablets and weigh to determine the average weight of core tablets. Set 15 specified parameter and start coating. Continue coating till the desired weight gain is achieved. After completion of coating roll the tablets with the inlet temperature at 40°C-50°C for about 15 minutes for proper drying. Take 50 coated tablets and weigh to determine the average weight of coated tablets and calculate the percentage weight gain. 20
21
The camylofin coated tablets are then compressed using Diclofenac outer layer granules , with average weight of the tablets being 486.0mg±5%, diameter 12.00±0.5mm, thickness, 4.50mm-5.3 mm, hardness of NLT 30N, Friability NMT 1.0% w/w, Disintegration time NMT 15 minute.
Preparation of Diclofenac outer tablet granules 5
Dispense the raw materials under RLAF as per the quantity mentioned. Verify the weight of the dispensed raw material. Sift hydroxyl propyl cellulose thorough sieve of mesh size 40# by using vibro sifter and collect it in double line poly bag. Sift Diclofenac potassium through sieve of mesh size 40#/30#/20#/60#/22#/18#/16# by using vibro sifter. Mix pregelatinised starch and sodium starch glycolate and sift through sieve of 10 mesh size 40#/30#/20#/60#/22#/18#/16# by using vibro sifter. Sift microcrystalline cellulose through mesh size 40#/30#/20#/60#/22#/18#/16# by using vibro sifter.
Take 70%-100% of dispensed quantity of Isopropyl alcohol into SS container, add slowly pre-sifted hydroxyl propyl cellulose into the solution with continuous stirring and allow it stir to get clear solution. Transfer pre-sifted Diclofenac Potassium, sodium 15 starch glycolate, pregelatinised starch and microcrystalline cellulose in RMG and mix at slow speed of impeller for 10 minutes (range 5-20 minutes). Add binder to the mixed materials in the RMG at slow speed for 1 to 20 minutes, more preferably 2 to 5 minutes . After addition of binder, mix continuously with impeller and chopper at slow speed to get the desired ampere load. If required, add remaining quantity of 20
22
isopropyl alcohol to get the desired consistency and mix continuously with impeller and chopper at fast/slow speed to get the desired ampere load. Pass the obtained wet granules through multi mill using screen of 8.0 mm (4.0 mm to 12.0 mm) with forward orientation of knives at slow speed (Optional).
Load the wet granules or the sized wet granules (if wet milling done) in FBD bowl and 5 air dry in FBD for 10 minutes. Rake the mass intermittently in the FBD bowl. Then dry at 25°C-65°C more preferably 45°C-55°C inlet air temperature and outlet temperature 20°C-55°C more preferably 35°C-40°C till to get the LOD 1.0 to 5.5 % w/w more preferably 3.0% to 4.5% w/w with intermediate raking (by digital moisture analyzer on auto mode at 105°C). 10
Pass the dried granules through Vibro sifter using sieve of mesh size 16#/18#/22#/30#/ more preferably 20#. Pass the retained granules through multi-mill using screen of 1.0 mm/2.0 mm/2.5 mm/1.5mm with knives at forward orientation & slow speed and sifting through 16#/18#/22#/30#/ more preferably 20# if required. Now prepare the lubricant materials by mixing sodium starch glycolate, 15 Colloidol silicon dioxide, Crospovidone/croscarmellose sodium, Talcum Powder and divide the mixed material into three parts. Transfer one part of the mixed lubricants material and the dried and sized granules into a octagonal blender and repeat it further three times and start blending for 3-20 minutes more preferably 10 minutes.
23
Now add pre-sifted magnesium sterate and mix for 1-6 minutes more preferably 3 minutes.
Preparation of Inlay tablets
The Diclofenac granules are firstly filled into the die cavity then coated (inner core) camolyfin tablets are placed over it and compressed to form inlaytablet. 5
Inlay tablet is firstly seal-coated by using Instamoist Shield (IC-MS-2398) (0.1%-2.5% w/w) of inlay tablet. After seal coating the tablet is coated by using Instacoat T2F (A17D20156) (0.5%-5.0 w/w)%.The coated tablets are then polished by using Stearic acid/carnauba wax (0.05-0.5% w/w) using solvent Isopropyl alcohol/ methylene chloride/ both. 10
Example 4- Stability, dissolution and disintegration data of Formulation as per example 1
a) Stability Condition: 25 °C±2 °C/60%±5%RH
Acceptance criteria
Initial testing
1st Month
3rd Month
Disintegration
Not more than 30min
16 minute 56 second
16 minute 41 second
16 minute 58 second
Dissolution
Camylofin Dihydrochloride
Not less than 70.0% in 60 minutes
Avg: 101.61%
Min: 92.08%
Avg: 102.44%
Min: 97.89%
Max: 108.31%
Avg: 103.20%
Min:97.72%
Max:108.17%
24
Max: 106.39%
Diclofenac
Not less than 70.0% in 60 minutes
Avg: 97.37%
Min:95.52%
Max:98.64%
Avg: 98.00%
Min: 93.38%
Max:100.31%
Avg: 93.56%
Min: 89.20%
Max: 97.86%
Assay
Camylofin dihydrochloride
Not less than 45.00mg and not more than 55.00mg
50.12mg
50.35mg
51.45mg
Diclofenac
Not less than 45.00mg and not more than 55.00mg
49.92mg
50.31mg
48.93mg
Impurity
Diclofenac related impurity-A
NMT 1.0%
Not detected
Not detected
Not detected
Single maximum unknown impurity
NMT 0.5%
0.080%
0.100%
0.158%
Total impurities
NMT 2.0%
0.224%
0.376%
0.498%
b) Stability condition: 30 °C±2 °C/75%±5%RH
Acceptance criteria
Initial testing
1st Month
3rd Month
Disintegration
Not more than 30min
16 minute 56 second
16 minute 08 second
16 minute 55 second
Dissolution
Camylofin Dihydrochloride
Not less than 70.0%
Avg: 101.61%
Avg: 99.09%
Min: 94.93%
Avg: 102.54%
Min:92.93%
25
in 60 minutes
Min: 92.08%
Max: 106.39%
Max: 107.42%
Max:112.04%
Diclofenac
Not less than 70.0% in 60 minutes
Avg: 97.37%
Min:95.52%
Max:98.64%
Avg: 96.26%
Min: 94.53%
Max:98.60%
Avg: 94.06%
Min: 85.92%
Max: 97.42%
Assay
Camylofin dihydrochloride
Not less than 45.00mg and not more than 55.00mg
50.12mg
49.85mg
50.94mg
Diclofenac
Not less than 45.00mg and not more than 55.00mg
49.92mg
50.32mg
49.92mg
Impurity
Diclofenac related impurity-A
NMT 1.0%
Not detected
Not detected
Not detected
Single maximum unknown impurity
NMT 0.5%
0.080%
0.100%
0.278%
Total impurities
NMT 2.0%
0.224%
0.385%
0.606%
c) Stability conditions: 40 °C±2 °C/75%±5%RH
Acceptance criteria
Initial testing
1st Month
3rd Month
Disintegration
Not more than 30min
16 minute 56 second
16 minute 22 second
18 minute 10 second
Dissolution
Camylofin Dihydrochloride
Not less than 70.0% in 60 minutes
Avg: 101.61%
Min: 92.08%
Max: 106.39%
Avg: 100.50%
Min: 96.11%
Max: 105.24%
Avg: 102.41%
Min:97.24%
Max:107.91%
Diclofenac
Not less than 70.0% in 60 minutes
Avg: 97.37%
Min: 95.52%
Max: 98.64%
Avg: 95.31%
Min: 90.66%
Max:99.98%
Avg: 92.80%
Min: 86.13%
Max:97.17%
Assay
Camylofin dihydrochloride
Not less than 45.00mg and not more than 55.00mg
50.12mg
49.87mg
49.00mg
Diclofenac
Not less than 45.00mg and not more than 55.00mg
49.92mg
49.58mg
48.72mg
Impurity
Diclofenac related impurity-A
NMT 1.0%
Not detected
Not detected
0.009%
Single maximum unknown impurity
NMT 0.5%
0.080%
0.279%
0.350%
Total impurities
NMT 2.0%
0.224%
0.555%
0.890% ,CLAIMS:An oral composition comprising an inner core tablet comprising Camylofin or pharmaceutically acceptable salts and an outer tablet comprising Diclofenac or pharmaceutically acceptable salts wherein the outer tablet is compressed over the inner core in such a way that top surface of the inner core is exposed. 5
2. An oral composition as claimed in claim 1 is an inlayed tablet comprising:
iv) an inner core tablet comprising camylofin dihydrochloride and pharmaceutically acceptable excipients and;
v) outer tablet compressed over the inner core tablet, wherein the outer tablet comprises of Diclofenac potassium and pharmaceutically acceptable 10 excipients
wherein one surface of the inner core tablet is completely or partially exposed.
3. An inlayed tablet as claimed in claim 1-2, Diclofenac potassium is present in an amount ranging from about 20-100 mg and camylofin dihydrochloride is 15 present in an amount ranging from about 20-100 mg.
4. An inlay tablet as claimed in claim 2 comprises an inner core tablet further comprising
i. 30-40 wt.% camylofin dihydrochloride as an active ingredient based on uncoated weight of inner core tablet and; 20
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ii. 35-40 wt.% one or more diluent based on uncoated weight of inner core tablet and;
iii. 2-6 wt.% one or more disintegrant based on uncoated weight of inner core tablet and;
iv. 1-5 wt.% one or more anti-adherent based on uncoated weight of 5 inner core tablet and;
v. 1-5 wt.% one or more glidant based on uncoated weight of inner core tablet and;
vi. 2-6 wt.% one or more lubricant based on uncoated weight of inner core tablet. 10
5. An inlay tablet as claimed in claim 5 comprises an inner core tablet further comprising:
i. 39.62 wt.% camylofin dihydrochloride as an active ingredient based on uncoated weight of inner core tablet and;
ii. 44.15 wt.% one or more diluent based on uncoated weight of inner core 15 tablet and;
iii. 5.30 wt.% crospovidone and 3.78 wt.% croscarmellose sodium as disintegrant based on uncoated weight of inner core tablet and;
iv. 1.50 wt.% colloidal silicon dioxide as anti-adherent based on uncoated weight of inner core tablet and; 20
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v. 1.50 wt.% talcum as glidant based on uncoated weight of inner core tablet and;
vi. 4.15 wt.% magnesium stearate as lubricant based on uncoated weight of inner core tablet
6. An inlay tablet as claimed in claim 2 comprises an outer core tablet further 5 comprising
i. 10-15 wt.% Diclofenac potassium as an active ingredient based on uncoated weight of outer tablet and;
ii. 40-45 wt.% one or more diluent based on uncoated weight of outer tablet and; 10
iii. 2-6 wt.% one or more disintegrant based on uncoated weight of outer tablet and;
iv. 25-30 wt.% one or more diluent based on uncoated weight of outer tablet and;
v. 0.2-2 wt.% one or more anti-adherent based on uncoated weight of 15 outer tablet and;
vi. 0.2-2 wt.% one or more glidant based on uncoated weight of outer tablet and;
vii. 1-5 wt.% one or more lubricant based on uncoated weight of outer tablet. 20
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7. An inlay tablet as claimed in claim 7 comprises an outer core tablet comprising:
i. 14.28 wt.% Diclofenac potassium as an active ingredient based on uncoated weight of outer tablet and;
ii. 42.42 wt.% microcrystalline cellulose as diluent based on uncoated weight of outer tablet and; 5
iii. 5.72 wt.% sodium starch glycolate and 2.85 wt.% crospovidone as disintegrant based on uncoated weight of outer tablet and;
iv. 28 wt.% Pregelatinised starch as diluent based on uncoated weight of outer tablet and;
v. 0.57 wt.% colloidal silicon dioxide as anti-adherent based on uncoated 10 weight of outer tablet and
vi. 0.30 wt.% talcum as glidant based on uncoated weight of outer tablet and
vii. 1.14 wt.% magnesium stearate as lubricant based on uncoated weight of outer tablet 15
8. A process of preparing an inner tablet as claimed in previous claim comprises following process:
i. Mixing Camylofin with diluent, one or more disintegrant, anti-adherent, glidant and lubricant by dry mixing or blending in a blender.
ii. The premix was lubricated with lubricant and blended for few minutes. 20
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iii. The mixture was then compressed with compressing machine. The compressed tablet was further coated with seal coating and film coating material.
9. A process of preparing an outer tablet as claimed in previous claim comprises following process: 5
i. Sift binder and diclofenac potassium separately through a sieve with help of vibro sifter and
ii. Mix diluent and disintegrant and sift through sieve and;
iii. Prepare binder solution with continuous stirring to obtain clear solution and; 10
iv. Mix pre-sifted Diclofenac potassium, disintegrant and diluent in rapid mixer granulator and;
v. Mix binder solution to rapid mix granulator for few minutes to obtain wet granules and;
vi. Dry the wet granules in FBD bowl and air dry in FBD for 10 minutes and; 15
vii. Lubricate the dry granules by mixing disintegrant, anti-adherent, disintegrant, glidant to obtain outer tablet granules.
viii. The outer tablet granules were filled into die cavity then inner tablet was placed over the granules and compressed to form inlay tablet. The inlay tablet was further coated with suitable coating materials. 20
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10. An inlay tablet as claimed in previous claims is used for the treatment of abdominal pain and cramp.
Dated this 12th of July’ 2023

For Akums Drugs and Pharmaceuticals Limited
Siddhartha Dulakakhoria (Authorized representative for Applicant)