EXTENDED RELEASE TABLETS OF CLARITHROMYCIN
Field of the Invention
The present invention relates to extended release tablets for oral administration
comprising clarithromycin and a pharmaceutically acceptable carrier, and processes for
their preparation.
Background of the Invention
Oral ingestion is one of the primary routes used for drug administration. This route
provides a convenient method of effectively achieving both local and systemic effects. In
conventional oral drug delivery systems there is little or no control over the release of the
drug and an effective concentration can only be maintained by repeated administrations.
Controlled release systems provide a uniform concentration of drug at the absorption site
for an extended period of time and thus, after absorption, allow maintenance of plasma
concentrations within a desired therapeutic range. This reduces the frequency of
administration.
The advantages of controlled release dosage forms for extended or sustained action
are well known. Some of them include a reduced daily dosage, improved patient
compliance, prevention of delay in recovery, avoidance of bacterial resistance and
ensuring successful therapy. The macrolide antibiotics are known for their anti-bacterial
activity against a number of micro-organisms and are typically administered as immediate
release (ER.) compositions two or three times a day for about 10 to 14 days.
Clarithromycin (6-O-methylerythromycin A), in particular, has a very bitter metallic taste
which can result in poor compliance of the dosing regimen or selection of another
therapeutic agent, possibly making it a less effective therapeutic agent.
An approach to address the possible non-compliance with the regimen is to
develop controlled release solid preparations containing erythromycin derivatives.
Unfortunately the properties of these macrolides, like many other poorly soluble basic
drugs, do not allow them to be incorporated in a single oral dosage form or to provide a
controlled efficient release of drug throughout a 24 hr period with reproducible
bioavailability. The main reason for this is that erythromycin derivatives are slightly
alkaline, practically water insoluble, acid-sensitive drugs. A basic drug's solubility
decreases with an increasing pH as it proceeds distally towards the large intestine (pH 6 to
8). It is soluble in stomach (pH 1.2) and upper or proximal region of small intestine (pH
5). Thus, a poorly soluble basic drug will lead to less drug being available for absorption
in the lower or distal intestine. Moreover, a daily dose of 500-1000 mg of clarithromycin
has to be incorporated in a relatively small matrix in order to allow for swallowing; this
leaves relatively little room for optimization of the biopharmaceutical and
physicochemical properties of a formulation.
Summary of the Invention
In one general aspect there is provided an extended release tablet of clarithromycin
for oral administration. The extended release tablet includes clarithromycin and a
pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier includes a
mixture of lactose and microcrystalline cellulose in a ratio ranging from 3:1 to 1:3.
Embodiments of the pharmaceutical composition may include one or more of the
following features. For example, the clarithromycin may be between about 50% to about
75% w/w of the total tablet weight and the pharmaceutically acceptable carrier may be
present from about 20% to about 30% w/w of the total tablet weight.
The lactose includes one or more of anhydrous lactose, spray-dried lactose and
lactose monohydrate.
The extended release tablet may further include one or more rate-controlling
polymers and one or more pharmaceutically acceptable excipients. The rate-controlling
polymers may be one or more of carbohydrate gums, polyuronic acid salts, cellulose
ethers, acrylic acid polymers and mixtures thereof. The carbohydrate gums may be one or
more of xanthan gum, tragacanth gum, gum karaya, guar gum, acacia, gellan and locust
bean gum. The polyuronic acid salts may be one or more of sodium alginate, potassium
alginate and ammonium alginate. The cellulose ethers may be one or more of
hydroxypropyl methylcellulose, hydroxypropyl cellulose and hydroxyethyl cellulose. The
acrylic polymer may be one or both of polyacrylic polymer and carboxy vinyl polymer.
The rate controlling polymers may be present from about 0.1% to about 4.5% w/w of total
tablet weight.
The pharmaceutically acceptable excipients may be one or more of binders,
lubricants, glidants, colorants and flavoring agents.
The binders may be one or more of starch, sugars, gums, low molecular weight
hydroxypropyl methylcellulose, polyvinyl pyrrolidone and hydroxypropyl cellulose.
The lubricants may be one or more of talc, magnesium stearate, calcium stearate,
polyethylene glycol, hydrogenated vegetable oils, stearic acid, sodium stearyl fumarate
and sodium benzoate.
The glidants may be one or both of colloidal silicon dioxide and talc.
The extended release tablet may further include one or more of omeprazole,
metronidazole, amoxicillin, rifampicin, lansoprazole, ciprofloxacin, ethambutol and
ritonavir.
In another general aspect there is provided a process for the preparation of
extended release tablets of clarithromycin for oral administration. The process includes
blending clarithromycin, a pharmaceutically acceptable carrier, one or more ratecontrolling
polymers and one or more binders to form a blend; screening the blend;
lubricating the blend; compressing the blend to form tablets; and optionally coating the
tablets. The pharmaceutically acceptable carrier comprises a mixture of lactose and
microcrystalline cellulose in a ratio ranging from 3:1 to 1:3.
In another general aspect there is provided process for the preparation of extended
release tablets of clarithromycin for oral administration. The process includes blending
clarithromycin, a pharmaceutically acceptable carrier, one or more rate-controlling
polymers and one or more binders to form a blend; compacting the blend to form granules;
sizing the granules; lubricating the granules; compressing to form tablets; and optionally
coating the tablets. The pharmaceutically acceptable carrier comprises a mixture of
lactose and microcrystalline cellulose in a ratio ranging from 3:1 to 1:3.
Embodiments of the process may include one or more of the following features.
For example, the granulation technique used may be wet or dry granulation.
In another general aspect there is provided a method of treatment for bacterial
infections in a mammal in need of treatment. The method includes administering an
extended release tablet of clarithromycin that includes clarithromycin and a
pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier includes a
mixture of lactose and microcrystalline cellulose in a ratio ranging from 3:1 to 1:3.
Embodiments of the method may include one or more of the following features.
For example, the extend release tablet may further include one or more of omeprazole,
metronidazole, amoxicillin, rifampicin, lansoprazole, ciprofloxacin, ethambutol and
ritonavir.
Detailed Description of the Invention
The inventors have surprisingly now formulated extended release tablets of
clarithromycin. The tablets include clarithromycin, one or more rate-controlling polymers
and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier
includes a mixture of lactose and microcrystalline cellulose in a ratio ranging from about
3:1 to about 1:3.
Various ratios of lactose and microcrystalline cellulose may be employed for
preparing tablets, such as about 1.5 to about 1, about 2.3 to about 1, about 3 to about 1 and
about 1 to about 3. Tablets containing only lactose were also prepared and it was found
that these tablets exhibited significantly higher Cmax (peak plasma concentration).
Solid dosage forms, the most commonly used method of drug delivery, have seen
an increasing sophistication in terms of functionality of the excipients. The transformation
of excipients from inert ingredients to functional components has occurred. It is
recognized that excipients are critical for stability, safety and performance of the dosage
forms. In the present invention, the importance of the ratio in which the two diluents or
fillers, lactose and microcrystalline cellulose are added, is emphasized. It is demonstrated
that the ratio has a significant effect on the bioavailability of the tablets and the ratio
ranging from about 3 to about 1 and from about 1 to about 3 exhibits extended release.
Suitable lactose includes one or more of anhydrous lactose, spray-dried lactose and
lactose monohydrate. For example, lactose monohydrate may be used.
Microcrystalline cellulose revolutionized tabletting because of its unique
compressibility and carrying capacity. It exhibits excellent properties as an excipient for
solid dosage forms. It has a high binding capability and creates tablets that are extremely
hard, stable, yet disintegrate rapidly. Other advantages include low friability, inherent
lubricity, and the highest dilution potential of all binders. These properties make
microcrystalline cellulose particularly valuable as a filler and binder for formulations
prepared by direct compression, although it is also used in wet or dry granulation. It is
commercially available under the tradename EMCOCEL™ from Edward Mendell Co.,
Inc. and as Avicel™ from FMC Corp.
The pharmaceutically acceptable carrier, which includes lactose and
microcrystalline cellulose, may be present at from about 20% to about 30% w/w of the
total tablet weight.
Suitable rate-controlling polymers of the extended release tablets include one or
more of carbohydrate gum, polyuronic acid salts, cellulose ethers, acrylic acid polymers
and mixtures, thereof. Suitable carbohydrate gums include one or more of xanthan gum,
tragacanth gum, gum karaya, guar gum, acacia, gellan, locust bean gum and other
carbohydrate gums having similar properties. Suitable polyuronic acid salts include one or
more of alkali metal salts of alginic acid or pectic acid and mixtures thereof. Suitable
alkali metal salts of alginic acid that may be used include one or more of sodium alginate,
potassium alginate, ammonium alginate and other suitable alkali metal salts of alginic
acid. Suitable cellulose ethers include one or more of hydroxypropyl methyl cellulose,
hydroxypropyl cellulose and other suitable cellulose ethers. Suitable acrylic acid
polymers include any suitable polyacrylic acid polymers or carboxyvinyl polymers such as
those available under the brand name carbopol.
The one or more rate-controlling polymers may be present at a concentration from
about 0.1% to about 4.5%w/w of the total tablet weight.
In addition to the active, pharmaceutically acceptable carrier and one or more ratecontrolling
polymers, the extended release tablets may additionally contain one or more
pharmaceutically acceptable excipients including one or more of binders, lubricants,
glidants, colorants and flavoring agents.
Suitable binders include one or more of starch, sugars, gums, low molecular weight
hydroxypropyl methylcellulose, polyvinyl pyrrolidone, polyethylene glycols, polyvinyl
acetate and hydroxypropyl cellulose.
Suitable lubricants include one or more of talc, magnesium stearate, calcium
stearate, polyethylene glycol, hydrogenated vegetable oils, stearic acid, sodium stearyl
fumarate and sodium benzoate.
Suitable glidants include colloidal silicon dioxide (aerosil) or talc.
Suitable coloring or flavoring agents include those approved for use by the United
States Food and Drug Administration (FDA) and are well known to those skilled in the art.
Also provided is a process for the preparation of extended release tablets of
clarithromycin that include clarithromycin and a pharmaceutically acceptable carrier. The
pharmaceutically acceptable carrier includes a mixture of lactose and microcrystalline
cellulose in a ratio ranging from about 3:1 to about 1:3.
The tablets may be prepared by direct compression. The clarithromycin may be
blended with one or more rate-controlling polymers and a pharmaceutically acceptable
carrier which includes a mixture of lactose and microcrystalline cellulose and one or more
pharmaceutically acceptable excipients. This blend is screened and compressed after
lubrication.
The tablets may also be prepared by wet granulation or dry granulation. The
clarithromycin may be blended with one or more rate-controlling polymers and a
pharmaceutically acceptable carrier which includes a mixture of lactose and
microcrystalline cellulose and one or more pharmaceutically acceptable excipients. This
blend is then granulated with a suitable binder solution to obtain granules. The granules
are further lubricated and compressed.
In one embodiment, the process of preparing the extended release tablets of
clarithromycin includes blending clarithromycin, a pharmaceutically acceptable carrier,
which includes lactose and microcrystalline cellulose in a ratio ranging from 3:1 to 1:3,
one or more rate-controlling polymers and one or more binders; screening the blend;
lubricating the blend; compressing the blend to form tablets; and optionally coating the
tablets.
In another embodiment, the process of preparing the extended release tablets of
clarithromycin includes blending clarithromycin, a pharmaceutically acceptable carrier,
which includes lactose and microcrystalline cellulose in a ratio ranging from 3:1 to 1:3
and one or more rate-controlling polymers; compacting the blend, screening into granules;
lubricating the granules; compressing to form tablets; and optionally coating the tablets.
In another embodiment, the process of preparing the extended release tablets of
clarithromycin includes blending clarithromycin, a pharmaceutically acceptable carrier,
which includes lactose and microcrystalline cellulose in a ratio ranging from 3:1 to 1:3 and
one or more rate-controlling polymers; granulating the blend with a solution of binder;
drying the granules, screening the granules, lubricating the granules; compressing the
granules to form tablets; and optionally coating the tablets.
Also provided is a method of treating a bacterial infection. The method includes
administering extended release tablets of clarithromycin which include clarithromycin and
a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier
includes a mixture of lactose and microcrystalline cellulose in a ratio ranging from 3:1 to
1:3.
The method of treating may further include concurrently administering one or
more of omeprazole, metronidazole, amoxicillin, rifampicin, lansoprazole, ciprofloxacin,
ethambutol, and ritonavir with clarithromycin.
The following examples are provided to illustrate various implementations of the
invention and are not intended to limit it.
EXAMPLES 1- 5
Preparation of extended release tablets of Clarithromycin
S.No.
1
2
3
4
5
6
7
8
9
10
Ingredients
Clarithromycin
Hydroxypropyl
methylcellulose
Lactose
Microcrystalline
cellulose
Polyvinylpyrrolidone
Sodium Stearyl
Fumarate
Talc
Magnesium Stearate
Colloidal silicon
dioxide
Opadry
Ratio of lactose and
microcrystalline
cellulose
Percent w/w
Ex-1
61.5
4.2
6.5
19.5
1.4
2.0
1.8
0.5
0.6
2.0
1:3
Ex-2
61.5
4.2
19.5
6.5
1.4
2.0
1.8
0.5
0.6
2.0
3:1
Ex-3
61.0
4.2
15.6
10.4
1.4
2.0
1.8
0.5
0.6
2.0
1.5:1
Ex-4
61.0
4.2
18.3
7.8
1.4
2.0
1.8
0.5
0.6
2.0
2.33:1
Ex-5
57.7
4.0
30.4
-
1.35
2.0
1.65
0.35
0.55
2.0
-
Procedure:
Clarithromycin, hydroxypropyl methylcellulose, polyvinyl pyrrolidone,
microcrystalline cellulose and lactose were sieved through a British Standard Sieve (BSS)
18 mesh sieve, blended together and granulated with binder solution. The resulting
granulate was dried in a fluid bed drier. The dried granules were sized and lubricated with
the remaining ingredients and compressed to form tablets. The tablets were coated with
opadry dispersion.
Pharmacokinetics
A single dose bioavailability study was conducted under a fasting state to
determine the concentration - time plasma profile on 20 healthy subjects. Clarithromycin
ER tablets 500 mg prepared according to Examples 3 and 4 were compared with
Clarithromycin extended release 500 mg tablets (Biaxin XL tablets manufactured by
Abbott Laboratories, USA and Klaricid XL tablets manufactured by Abbott Laboratories,
UK). There was a washout period of 3 days.
Values for pharmacokinetic parameters, including observed CmaX, AUCo-t and
AUCo-cc, were calculated using standard non-compartmental methods. The results as
indicated by ratio of test to reference are shown in Table 1.
Reference A: Biaxin XL (500 mg) tablets, Mfd. By Abbott Laboratories, USA
Reference B: Klaricid XL (500 mg) tablets, Mfd. By Abbott Laboratories, UK
Test C: Clarithromycin extended release tablets (Example 4)
Test D: Clarithromycin extended release tablets (Example 3)
As is evident from Table 1, Clarithromycin ER tablets (formulated as per Examples
3 and 4) are suitable for administration to a patient for extended release.
Similar studies were carried out in which 500 mg Clarithromycin ER tablets were
prepared according to Example 5.
Values for the pharmacokinetic parameters, including observed CmaX, AUCo-t and
AUCo-cc, were calculated using standard non-compartmental methods. The results are
indicated by the ratio of test to reference are shown in Table 2.
Reference R: Biaxin XL (500 mg) tablets, Mfd. By Abbott Laboratories, USA
Test T: Clarithromycin extended release tablets (Example 5)
As evident from Table 2, the tablets prepared with lactose alone exhibited a
significantly higher Cmax.
While the present invention has been described in terms of its specific
embodiments, certain modifications and equivalents will be apparent to those skilled in the
art and are included within the scope of the present invention.

WE CLAIM:
1. An extended release tablet for oral administration comprising clarithromycin and a
pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier
comprises a mixture of lactose and micro-crystalline cellulose in a ratio ranging from 3: 1
to 1:3.
2. The extended release tablet according to claim 1, wherein the clarithromycin comprises
from about 50% to about 75% w/w of the total tablet weight.
3. The extended release tablet according to claim 1, wherein the pharmaceutically
acceptable carrier comprises from about 20% to about 30% w/w of the total tablet weight.
4. The extended release tablet according to claim 1, further comprising one or more ratecontrolling
polymers and one or more pharmaceutically acceptable excipients.
5. The extended release tablet according to claim 4, wherein the rate controlling polymers
comprise one or more of carbohydrate gums, polyuronic acid salts, cellulose ethers,
acrylic acid polymers and mixtures thereof.
6. The extended release tablet according to claim 4, wherein the rate controlling polymers
comprise about 0.1% to about 4.5% w/w of total tablet weight.
7. The extended release tablet according to claim 4, wherein the one or more
pharmaceutically acceptable excipients comprise one or more of binders, lubricants,
glidants, colorants and flavoring agents.
8. A process for the preparation of extended release tablets of clarithromycin for oral
administration, the process comprising:
blending clarithromycin, a pharmaceutically acceptable carrier, one or more ratecontrolling
polymers and one or more binders to form a blend;
screening the blend;
lubricating the blend;
compressing the blend to form tablets; and
optionally coating the tablets,
wherein the pharmaceutically acceptable carrier comprises a mixture of lactose and
microcrystalline cellulose in a ratio ranging from 3: 1 to 1: 3.
9. A process for the preparation of extended release tablets of clarithromycin for oral
administration, the process comprising:
blending clarithromycin, a pharmaceutically acceptable carrier, one or more ratecontrolling
polymers and one or more binders to form a blend;
compacting the blend to form granules;
sizing the granules;
lubricating the granules;
compressing to form tablets; and
optionally coating the tablets;
wherein the pharmaceutically acceptable carrier comprises a mixture of lactose and
microcrystalline cellulose in a ratio ranging from 3: 1 to 1: 3.
10. An extended release tablet of clarithromycin comprising clarithromycin and a
pharmaceutical carrier substantially as described and illustrated herein.