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Title:
LINCOMYCIN SUSTAINED RELEASE TABLETS 1000MG
Document Type and Number:
WIPO Patent Application WO/2019/234763
Kind Code:
A1
Abstract:
The present invention discloses lincomycin sustained release tablets. More particularly, the invention discloses sustained release tablets of lincomycin 1000mg for once a day administration.

Inventors:
MENEZES RASHMI (IN)
PINTO VINAY (IN)
KUMAR PANKAJ (IN)
NIMASE SOPAN (IN)
Application Number:
PCT/IN2019/050434
Publication Date:
December 12, 2019
Filing Date:
June 06, 2019
Export Citation:
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Assignee:
WALLACE PHARMACEUTICALS PVT LTD (IN)
International Classes:
C07H15/16; A61K9/20; A61K9/22; A61K9/30; A61K9/62
Foreign References:
IN2094MUM2015A
JP3893058B22007-03-14
TW200301139A2003-07-01
Attorney, Agent or Firm:
P., Aruna Sree (IN)
Download PDF:
Claims:
We claim,

1. A sustained release composition of lincomycin comprising;

a) a slow dissolving matrix consisting of,

i) Lincomycin in an amount of 60 to 70% by weight;

ii) Combination of High viscosity grade hydroxypropyl methylcellulose (HPMC) 100000 CPS and 200000 CPS as rate controlling polymer in an amount of 10 to 20% by weight;

iii) Microcrystalline cellulose as diluent in an amount of 10 to 15% by weight;

iv) Polyvinyl pyrrolidone as binder in an amount of 0.5 to 1% by weight; b) anionic copolymers as coating polymer in an amount of 1 to 1.5%; and c) one or more pharmaceutical carriers or excipients.

2. The sustained release composition as claimed in claim 1, wherein the combination of high viscosity grade HPMC 100000 CPSand HPMC 200000 CPS is in a ratio of 1 : 1.1 to 1 : 1.3.

3. The sustained release composition as claimed in claim 1, wherein the anionic copolymer is Methacrylic Acid-Methyl Methacrylate Copolymer (1 :2).

4. The sustained release composition as claimed in claim 1, wherein the pharmaceutical carriers or excipients are selected from the group consisting of lubricants, diluents, glidants, anti-adherents, colors, flavours, plasticizers etc.

5. The sustained release composition as claimed in claim 1, wherein the concentration of lincomycin is lOOOmg.

6. The sustained release composition as claimed in claim 1, wherein the composition exhibits dissolution release profile which is characterized by not more than 20% of the lincomycin released within zero to two hours; 10 % - 40% of the lincomycin released within zero to six hours; 35 % to 65% of the lincomycin released within zero to ten hours; 60 % to 85% of the lincomycin released within zero to fourteen hours; and not less than 80% of the lincomycin released within zero to twenty hours.

7. The sustained release composition as claimed in claim 1, wherein the composition has Lincomycin B impurity in not more than 5.0%.

8. A process for preparation of sustained release composition as claimed in claim 1, wherein the process comprising the steps of;

a) Sifting and mixing lincomycin; High viscosity grade HPMCs and Microcrystalline Cellulose;

b) Preparing binder solution by dissolving Polyvinyl Pyrrolidone in IP A; c) Granulating the mixture of step a) with the binder solution of step b) to obtain granules followed by drying and sieving the granules;

d) Lubricating the granules of step c) by adding the lubricants, glidants and anti-adherents followed by compression to obtain compressed tablets; and e) Preparing the coating solution by dissolving anionic copolymer, plasticizer, colorants and coating the tablets of step d) with the coating solution.

9. The process as claimed in claim 8, wherein, the High viscosity grade HPMC is a combination of HPMC 100000 CPs and 200000CPs in a ratio of 1 : 1 to 1 : 1.3.

10. The process as claimed in claim 8, wherein, the anionic copolymer is Methacrylic Acid-Methyl Methacrylate Copolymer (1 :2).

11. The process as claimed in claim 8, wherein, the lubricant is magnesium stearate, the plasticizer is Polyethylene Glycol and the colorant is Ferric Oxide Red.

Description:
“LINCOMYCIN SUSTAINED RELEASE TABLETS lOOOmg”

Technical filed:

The present invention relates to lincomycin sustained release tablets. More particularly, the invention relates to sustained release tablets of lincomycin lOOOmg for once a day administration.

Background and prior art:

Lincomycin Hydrochloride is a lincosamide antibiotic originally identified in actinomycete Streptomyces lincolnensis with activity against gram-positive cocci and anaerobic bacteria, known from l960s. Lincomycin hydrochloride is white crystalline powder and freely soluble in water.

The lincomycin hydrochloride is chemically known as Methyl 6,8-dideoxy-6-(l- methyl-trans-4-propyl-L-2-pyrolidinecarboxamido)-l-thio-D-er ythro-a-D-galacto- octopyranoside monohydrochloride monohydrate, shown below as formula I.

Formula I

Lincomycin indicated for serious infections due to susceptible strains of streptococci, pneumococci, and staphylococci. Lincomycin is also effective against other organisms including actinomycetes, mycoplasma, and some species of Plasmodium. Lincomycin inhibits protein synthesis in susceptible bacteria by binding to the 50 S subunits of bacterial ribosomes and prevents peptide bond formation. It is usually considered as bacteriostatic but may be bactericidal in high concentrations or when used against highly susceptible organisms.

Lincomycin is well absorbed in gastro intestinal tract when administered orally. However, food significantly delays and decreases absorption, the mean peak plasma level from a dose given immediately after a meal being only about half the fasting levels.

Lincomycin distributes widely and rapidly to most fluids and tissues except cerebrospinal fluid (CSF); high concentrations in bone, bile, and urine are reported. Like clindamycin. Lincomycin is metabolized in the liver and excreted in the bile. About 40% of an oral dose can be recovered from the feces. Less than 5% of an oral dose appears in the urine over 24 h, but up to 60% after intravenous administration, mostly in the first 4 h.

The recommended daily dose by WHO is about l .8g for oral as well as parenteral administration in a divided doses of 500mg for 2 to 4 times based on the severity of the infection. The peak serum concentration was observed within 2 to 4 hrs upon oral administration. The biological half-life of lincomycin after administration in a person with normal renal function is 5.4 ± 1.0 h. The serum half-life of lincomycin may be prolonged in patients with severe impairment of renal function, for example 10 to 20 hrs, compared to patients with normal renal function. In patients with abnormal hepatic function, serum half-life may be twofold longer than in patients with normal hepatic function. Haemodialysis and peritoneal dialysis are not effective in removing lincomycin from the serum. Tissue level studies indicate that bile is an important route of excretion.

It was further reported that the protein binding of the lincomycin decreases with increased plasma concentrations. Lincomycin is available with brand name(s) such as Lincocin; Lineorex, Linx etc. as a 5Q0mg capsule administered every 6 to 8 hrs.

There is very less literature available on lincomycin, its analogs, its salts & compositions.

US3304229 discloses pharmaceutical preparation which comprises novel pharmaceutical salts of lincomycin selected from the group consisting of lincomycin phenylsulfamate and lincomycin n-phenyl-n-alkyl-sulfamate in an amount of 100 to about 1000 mg, dispersed in a pharmaceutical earner.

US3539689 discloses compositions comprise 7-halo-lincomycin in an amount of 15-500 mg along with pharmaceutical carrier for oral and parenteral administration.

US3642987 discloses Lincomycin and tetracycline composition with ranges of lincomycin 5-95 parts (50-1000 mg) to tetracycline 95-5 parts (50-1000 mg)

US 3509256 disclose compositions comprising lincomycin-2-phosphate.

CN104095871A describes veterinary ' injection containing lincomycin hydrochloride and spectinomycin sulphate.

Lincomycin is conventionally administered as 500mg capsules in the form of immediate release dosage form with peak serum concentration within 2 to 4 hrs upon oral administration. The rapid and wide distribution of this drug makes it the best choice for the treatment of infections arising out of streptococci, pneumococci, and staphylococci bacterial species.

The biggest disadvantage of the conventional immediate release formulation as mentioned above lies in the biological half-life of the lincomycin and its presence in the body over a longer period. As described above, the biological half-life of lincomycin after administration in a person with normal renal function is 5.4 ± 1.0 h. In patients with abnormal hepatic function, serum half-life may be twofold longer than in patients with normal hepatic function.

It has been observed by the present inventors that the conventional immediate release dosage form of Lincomycin Hydrochloride has few limitations. For example, administering 500 mg capsule every 6 or 8 hourly would amount to dose dumping leading to increased plasma concentration due to the longer biological half-life and also due to hepatic metabolism of the lincomycin, even in a person with normal renal function.

Additional reported disadvantage is that the decreased protein binding of the lincomycin with increased plasma concentrations, leads to lesser absorption and higher excretion of the drug in addition to development of bacterial resistance. However, none of the prior arts or any research groups have ever tried to address these issues by providing a suitable solution so as to increase the effectiveness of lincomycin and patient compliance with safety.

Therefore, there remains a need in the art to provide sustained release tablet of lincomycin that will take care of issues with multiple dosing and improved protein binding with constant serum concentrations.

Accordingly, the objective of the present invention is to provide sustained release lincomycin tablets of lOOOmg that will control the release of the lincomycin over a period of 20 to 24 hrs and can maintain constant serum concentrations thereby improved therapeutic effect.

Summary of the invention:

In accordance with the above objective, the invention provides sustained release tablets of lincomycin. In an aspect, the sustained release tablets of lincomycin Hydrochloride comprise lincomycin in an amount of lOOOmg for once a day administration.

According to the invention, the sustained/controlled drug delivery of Lincomycin Hydrochloride helps in maintenance of constant plasma drug concentration and retards the release rate of drug thereby extending the duration of action. The sustained release tablets of lincomycin provide patient compliance by reducing the multiple dosing, see-saw fluctuations and maintain constant serum plasma concentration by providing sustained delivery of the drug for up 20 to 24 hrs thereby exerts desired therapeutic effect.

Accordingly, the present invention provides sustained release composition which comprises;

a) a slow dissolving matrix consisting of,

i) Lincomycin in an amount of 60 to 70% by weight;

ii) Combination of Hydroxypropyl methyl cellulose 100000 Cps and Hydroxypropyl methyl cellulose 200000 Cps as rate controlling polymer in an amount of 10 to 20% by weight;

iii) Microcrystalline cellulose as diluent in an amount of 10 to 15% by weight; iv) Polyvinyl pyrrolidone as binder in an amount of 0.5 to 1% by weight; b) anionic copolymers as coating polymer in an amount of 1 to 1.5%; and c) one or more pharmaceutical carriers or excipients.

The combination of high viscosity grade Hydroxypropyl methyl cellulose, according to the invention is in the ratio of 1 : 1.1 to 1 : 1.3.

The anionic copolymer according to the invention is Methacrylic Acid-Methyl Methacrylate Copolymer (1 :2), used for coating of the tablets.

The concentration of lincomycin is lOOOmg in the sustained release composition, meant for once a day administration. The pharmaceutical carriers or excipients may be selected from the group consisting of lubricants, diluents, glidants, anti-adherents, colors, flavours, plasticizers etc.

The sustained release composition according to the invention wherein the composition exhibits dissolution profile which is characterized by not more than 20% of the lincomycin released within zero to two hours; 10 % - 40% of the lincomycin released within zero to six hours; 35 % to 65% of the lincomycin released within zero to ten hours; 60 % to 85% of the lincomycin released within zero to fourteen hours; and not less than 80% of the lincomycin released within zero to twenty hours.

The composition has Lincomycin B impurity in not more than 5.0%, indicating the long term stability of the composition.

In another aspect, the invention provides a process for preparation of sustained release composition wherein the process comprising the steps of;

a) Sifting and mixing lincomycin, High viscosity grade HPMCs and Microcrystalline Cellulose;

b) Preparing binder solution by dissolving Polyvinyl Pyrrolidone in IP A;

c) Granulating the mixture of step a) with the binder solution of step b) to obtain granules followed by drying and sieving the granules;

d) Lubricating the granules of step c) by adding the lubricants, glidants and anti adherents followed by compression to obtain compressed tablets; and e) Preparing the coating solution by dissolving anionic copolymer, plasticizer, colorants and coating the tablets of step d) with the coating solution.

The combination of High viscosity grade HPMCs as used in the process of the present invention is the combination of HPMC 100000 CPs and 200000CPs; the anionic copolymer is Methacrylic Acid-Methyl Methacrylate Copolymer (1 :2); the lubricant is magnesium stearate, the plasticizer is Polyethylene Glycol and the colorant is Ferric Oxide Red. Detailed description:

The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

Accordingly, the invention provides sustained release tablets of lincomycin. In an aspect, the sustained release tablets of lincomycin Hydrochloride comprise lincomycin in an amount of lOOOmg for once a day administration.

According to the invention, the sustained/controlled drug delivery of Lincomycin Hydrochloride helps in maintenance of constant plasma drug concentration and retards the release rate of drug thereby extending the duration of action.

The sustained release tablets of lincomycin provide patient compliance by reducing the multiple dosing, see-saw fluctuations and maintain constant serum plasma concentration by providing sustained delivery of the drug for up 20 to 24 hrs thereby exerts desired therapeutic effect.

For the development of sustained delivery of the highly soluble lincomycin hydrochloride for upto 20 to 24 hrs, a proper polymer matrix is needed to be prepared from which the drug release occurs by polymer swelling, polymer erosion, drug dissolution/diffusion mechanism. The present inventors have tried different polymers which include carbopol, high viscosity grades of HPMC and the combinations thereof.

In line with the above, in one embodiment, the matrix formulation was prepared with carbopol as shown in example 1. However, this formulation failed to achieve desired sustained release as shown in analysis report of example 1.

In another embodiment, the matrix formulation was prepared with HPMC. HPMC (hydroxy propyl methyl cellulose), available in various grades, is routinely used in the development of immediate and controlled released drug delivery. In accordance with this embodiment, the present inventors have attempted the preparation of sustained release matrix using high viscosity grade HPMC 100000 cps as shown in example 2. However, HPMC 100000 cps grade is failed to provide desired sustained release of lincomycin as shown in example 2, instead this matrix release the drug as burst release.

Therefore, to circumvent the variability of drug release and to improve the consistency and sustainability of lincomycin drug release, in another embodiment, the matrix was prepared with the combination of HPMC lOOOOcps and HPMC 20000cps in 1 : 1 ratio as depicted in example 3. Although this matrix exhibits relatively better release characteristics, however, failed to provide desired sustained release of lincomycin as shown in example 3.

All the above experiments (examples 1, example 2 and example 3) have failed the required dissolution test, i.e., the release of the active shall not more be than 20% of Label claim at the end of 2 nd hr.

However, to the applicant’s surprise a modification in the ratio of both the high viscosity HPMCs results in desired sustained release and even the release was observed to be last up to 20 to 24 hrs (example 4 and another 2 reproducible batch as shown example 5 and example 6).

Accordingly, in a preferred embodiment, the combination of High viscosity grade hydroxypropyl methylcellulose 10000 cps and 200000 cps is used in a ratio of 1 : 1.1 to 1 : 1.3 to effectively control the delivery of the highly soluble lincomycin over period of 20 to 24 hrs.

In one preferred embodiment, the ratio of hydroxypropyl methylcellulose 10000 cps and hydroxypropyl methylcellulose 200000 cps is used in a ratio of 1 : 1.25. Accordingly, the present invention provides sustained release composition which comprises;

a) a slow dissolving matrix consisting of

i) Lincomycin in an amount of 60 to 70% by weight;

ii) Combination of High viscosity grade HPMCs as rate controlling polymer in an amount of 10 to 20% by weight;

iii) Microcrystalline cellulose as diluent in an amount of 10 to 15% by weight; iv) Polyvinyl pyrrolidone as binder in an amount of 0.5 to 1% by weight; b) anionic copolymers as coating polymer in an amount of 1 to 1.5%; and c) one or more pharmaceutical carriers or excipients.

The anionic copolymer according to the invention is Methacrylic Acid-Methyl Methacrylate Copolymer (1 :2).

The concentration of lincomycin is lOOOmg in the sustained release composition, for once a day administration.

The pharmaceutical carriers or excipients may be selected from the group consisting of lubricants, diluents, glidants, anti-adherents, colors, flavours, plasticizers etc.

The sustained release composition according to the invention (as per the examples 4 to 6) wherein the composition exhibits dissolution profile which is characterized by not more than 20% of the lincomycin released within zero to two hours; 10 % - 40% of the lincomycin released within zero to six hours; 35 % to 65% of the lincomycin released within zero to ten hours; 60 % to 85% of the lincomycin released within zero to fourteen hours; and not less than 80% of the lincomycin released within zero to twenty hours.

It can be reasonably concluded based on the consistent release profile, as demonstrated in the present invention that the sustained release tablets of lincomycin reduces see-saw fluctuations and can maintain constant serum plasma concentration thereby exerts desired therapeutic effect.

The composition is further characterized by having Lincomycin B impurity in not more than 5.0%, indicating good stability and shelf-life of the composition.

In another aspect, the invention provides a process for preparation of sustained release composition wherein the process comprising the steps of;

a) Sifting and mixing lincomycin; High viscosity grade HPMCs and Microcrystalline Cellulose;

b) Preparing binder solution by dissolving Polyvinyl Pyrrolidone in IP A;

c) Granulating the mixture of step a) with the binder solution of step b) to obtain granules followed by drying and sieving the granules;

d) Lubricating the granules of step c) by adding the lubricants, glidants and anti adherents followed by compression to obtain compressed tablets; and e) Preparing the coating solution by dissolving anionic copolymer, plasticizer, colorants and coating the tablets of step d) with the coating solution.

The High viscosity hydroxypropyl methylcellulose (HPMC) used as rate controlling polymer in the process of the invention, is the combination of HPMC 100000 CPs and HPMC 200000CPs in a ratio of 1 : 1 to 1 : 1.3; more preferably in a ratio of 1 : 1.25.

The anionic copolymer is Methacrylic Acid-Methyl Methacrylate Copolymer (1 :2); the lubricant is magnesium stearate, the plasticizer is Polyethylene Glycol and the colorant is Ferric Oxide Red.

The process of the present invention is simple and easier to scale up for industrial production of lincomycin sustained release tablets. The process of the present invention is cost effective as it does not require costly equipment and is easier for industrial scale up. In yet another embodiment, the invention provides long term stability data conducted under accelerated conditions at 40°C (±2 °C),75% RH (± 5% RH) of the coated tablets along with its dissolution profile, as depicted in examples 4 to 6. According to assay, the coated tablets of the invention exhibit long term stability and consistent release profile even after 3 months. After 3 months stability studies of these tablets show lincomycin B impurity substantially the same and within the acceptable limits i.e., not more than 5%.

The following examples (example 4 to 6), which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.

Examples

Example 1

Lincomycin hydrochloride lOOOmg tablet formulation with Carbopol

Q.s = Quantity Sufficient

* Actual quantity of Lincomycin Hydrochloride may be varied on the Water and Assay content.

# The final quantity of active to be compensated with diluent. Release and content characteristics of example 1

Conclusion: Product fails as per specification in dissolution test Example 2

Lincomycin hydrochloride lOOOmg tablet formulation with HPMC 100000 cps

Q.s = Quantity Sufficient

* Actual quantity of Lincomycin Hydrochloride may be varied on the Water and Assay content.

# The final quantity of active to be compensated with diluent.

Release and content characteristics of example 2

Conclusion: Product fails as per specification in dissolution test

Example 3

Lincomycin hydrochloride lOOOmg tablet formulation with HPMC 100000 cps and 20000CPS in 1:1 ratio

Q.s = Quantity Sufficient

* Actual quantity of Lincomycin Hydrochloride may be varied on the Water and Assay content.

# The final quantity of active to be compensated with diluent.

Release and content characteristics of example 3

Conclusion: Product fails as per specification in dissolution test

Example 4

Lincomycin hydrochloride lOOOmg tablet formulation

Q.s = Quantity Sufficient

* Actual quantity of Lincomycin Hydrochloride may be varied on the Water and Assay content.

# The final quantity of active to be compensated with diluent. Note : Two more reproducible batches are prepared as per example 4 by considering the same as final formulation and subjected them to stability studies, as shown in examples 5 & 6.

Procedure:

a) Sifting and mixing lincomycin; Hydroxypropyl Methylcellulose 10000CPS and 200000CPS; Microcrystalline Cellulose;

b) Preparing binder solution by dissolving Polyvinyl Pyrrolidone in IP A;

c) Granulating the mixture of step a) with the binder solution of step b) to obtain granules followed by drying and sieving the granules;

d) Lubricating the granules of step c) by adding the lubricants, glidants and anti adherents followed by compression to obtain compressed tablets; and e) Preparing the coating solution by dissolving anionic copolymer, plasticizer, colorants and coating the tablets of step d) with the coating solution.

Release and content characteristics of example 4

Stability Data of the Example 4

Product Name: LINCOMYCIN SUSTAINED RELEASE TABLETS 1000 mg Pack: Blister of lOTablets (PVC-PVDC)

Storage Condition: Accelerated Data [40°C (±2 °C),75% RH (± 5% RH) ]

Example 5

Initial and Stability Data of reproducible batch as Example 4

Product Name: LINCOMYCIN SUSTAINED RELEASE TABLETS 1000 mg Pack: Blister of lOTablets (PVC-PVDC)

Storage Condition: Accelerated Data [40°C (±2 °C),75% RH (± 5% RH) ]

Example 6

Initial and Stability Data of reproducible batch as Example 4

Product Name: LINCOMYCIN SUSTAINED RELEASE TABLETS 1000 mg Pack: Blister of lOTablets (PVC-PVDC) Storage Condition: Accelerated Data [40°C (±2 °C),75% RH (± 5% RH) ]