This application is a continuation-in-part of patent application, filed April 3, 2003, which claims the benefit of Indian Provisional Application No. 425/DEL/2002, filed on April 4, 2002.
In general, it is known that the absorption and bioavailability of any particular therapeutic agent can be affected by numerous factors when dosed orally. Such factors include the presence of food in the gastrointestinal (Gl) tract because, in general, the gastric residence time of a drug is usually significantly longer in the presence of food than in the fasted state. If the bioavailability of a drug is affected beyond a certain point due to the presence of food in the Gl tract, the drug is said to exhibit a "food effect".
Clarithromycin presents a peculiar problem for the formulator as it has greater solubility in the upper part of the gastrointestinal tract (GIT) but is highly unstable at the acidic pH conditions in the upper part of GIT, and while its stability is good at alkaline pH of the lower intestine (pH 6.0 to 8.0), its solubility is poor there. This results in poor bioavailability of Clarithromycin. Food effect is also prominent in case of clarithromycin, as it stays in the stomach for a period of 2-3 hours in the presence of food. However, in fasting conditions it reaches the intestine within 30 minutes of administration, where it has poor bioavailability.
Our co-pending application describes extended release tablets of clarithromycin exhibiting improved dissolution and absorption characteristics, wherein the tablets were prepared using micronized clarithromycin. The extended release tablets featured an area-under-the-curve (AUC) comparable to the area-under-the-curve (AUC) of a twice-daily immediate release dosage form. These extended release tablets were bioequivalent when administered during fed-state.
Surprisingly, the inventors have discovered that extended release tablets prepared using micronized clarithromycin which has been processed with suitable wetting agents, results in improved dissolution and absorption characteristics even when the tablets are administered in fasting conditions.
Use of wetting agent also helps in incorporating a very high content of the active, over 70% w/w in the tablets, while maintaining the tablet size that is acceptable and easy to swallow. Compositions with high drug content leave little room for excipients, especially where the
size of the dosage form is a constraint. In clarithromycin compositions, where more than 70% w/w active is to be incorporated without increasing the size of the dosage form, the high concentration of the hydrophobic active acts as a barrier for aqueous media. However, this problem can be overcome by treating clarithromycin with a small amount of a wetting agent. And consequently, more than 70% w/w of the active may be incorporated in a single tablet without further increasing the size of the tablet.
Therefore, in one general aspect, there are provided extended release tablets of clarithromycin, comprising more than 70% w/w of clarithromycin.
In another general aspect, there are provided extended release tablets of clarithromycin, comprising from about 70% to about 90%w/w of clarithromycin.
According to another general aspect, there are provided extended release clarithromycin tablets of 1000 mg strength, wherein the total weight of the tablet does not exceed 1400 mg.
According to another general aspect, there are provided extended release tablets of clarithromycin comprising micronized clarithromycin, wherein said micronized clarithromycin has been processed with a wetting agent.
According to another general aspect, there are provided extended release tablets of clarithromycin, comprising micronized clarithromycin having a particle size less than approximately 50 microns, particularly less than 35 microns; wherein said micronized clarithromycin has been processed with a wetting agent.
According to another general aspect, a process is provided for treating clarithromycin with a wetting agent.
According to another general aspect, extended release tablets may include one or more rate controlling polymers.
According to yet another aspect, the extended release tablets may exhibit improved absorption characteristics relative to a pharmaceutical composition of clarithromycin
without wetting agent. The extended release tablets exhibit an area-under-the-curve (ADC) comparable in fed as well as fasting states when compared with Biaxin XL tablets (extended release tablets; 2 X 500 mg), marketed by Abbott..
According to yet another aspect, extended release tablets may further include one or more of omeprazole, metronidazole, amoxicillin, rifampicin, lansoprazole, ciprofloxacin, ethambutol, and ritonavir. The clarithromycin and the one or more active ingredients may be combined in a single pharmaceutical composition.
According to another general aspect, extended release tablets may further include unmicronized clarithromycin, thereby forming a mixture of unmicronized and micronized clarithromycin.
In another general aspect, a process for preparing an extended release tablet of clarithromycin includes micronizing clarithromycin; processing the micronized active with a solution of a wetting agent; drying the wetted active; blending the active with one or more rate controlling polymers and pharmaceutically acceptable excipients; granulating the blend; and compressing to form a tablet.
Embodiments of the process may include one or more of the following features. For example, the clarithromycin may be micronized to have a particle size less than approximately 50 microns. Particularly, the clarithromycin may be micronized to have a particle size less than 35 microns. The clarithromycin may make up between approximately 100 mg and approximately 1000 mg of the tablet.
The clarithromycin may be micronized in an air jet mill and micronizing may include co-micronizing the clarithromycin with one or more pharmaceutical inert carriers. The pharmaceutically inert carrier may be one or more cellulose derivatives, silicate derivatives, and clays.
In another general aspect, a method of providing antibacterial activity to a mammal in need of treatment includes administering a pharmaceutical composition comprising micronized
clarithromycin, wetting agent, rate-controlling polymers and one or more pharmaceutically acceptable excipients.
The clarithromycin in the extended release tablets is taken to provide antibacterial activity may include at least some clarithromycin that has been micronized to have a particle size less than 50 microns, particularly less than 35 microns, and wetting agent. The clarithromycin may make up between approximately 100 mg and approximately 1000 mg of the extended release tablets. The method of treating may further include administering one or more of omeprazole, metronidazole, amoxicillin, rifampicin, lansoprazole, ciprofloxacin, ethambutol, and ritonavir with the micronized clarithromycin.
The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and claims.
Detailed Description
The advantages of controlled release products are well known in the pharmaceutical field and include the ability to maintain a desired blood level of a medicament over a comparatively longer period of time while increasing patient compliance by reducing the number of administrations necessary to achieve the same. These advantages have been attained by a wide variety of methods.
Oral extended release delivery systems should ideally be adaptable so that release rates and profiles can be matched to physiological and chronotherapeutic requirements. While many oral controlled and sustained release formulations are already known, certain drugs that are relatively insoluble in water and which further have relatively high dose requirements (based on weight) present formulation difficulties which render them unsuitable for inclusion in extended release formulations. Difficulties in preparing suitable extended release formulations of insoluble drugs are increased when the dose of the insoluble drug to be delivered to render a therapeutic effect over the desired period of time is relatively high, e.g., more than 500 mg.
In our co-pending patent application, we have described that extended release pharmaceutical compositions of clarithromycin could be prepared using micronized clarithromycin. These extended release compositions were found to possess improved dissolution and absorption characteristics and exhibited bioavailability comparable to two doses of immediate release formulations of clarithromycin. However, comparable results were obtained only in fed conditions.
The inventors nonetheless realized the desirability of dosage forms of clarithromycin having improved dissolution and absorption characteristics that can be administered once per day during fasted state also, and conducted research and development activities for developing such a clarithromycin formulation. As a result of these efforts, the inventors have surprisingly found that the dissolution and absorption characteristics of clarithromycin, as well as its bioavailability, can be increased by processing the micronized clarithromycin particles with sufficient amount of a wetting agent. Further, a large dose of the drug can be incorporated into a single tablet without increasing the size of the tablet.
The term "micronization" used herein means any process or methods by which the size of the particles is reduced. As also used herein, clarithromycin particles with reduced size are referred to as "micronized particles of clarithromycin" or "micronized clarithromycin".
The clarithromycin used in the pharmaceutical compositions described herein can be prepared by any known method, such as, for example, using either of the procedures disclosed in U.S. Patent No. 4,331,803 or U.S. Patent No. 4,672,109. Both of these patents are incorporated herein in their entirety by reference. Clarithromycin constitutes more than 70% w/w of the tablets; particularly, it constitutes 70-90% w/w of the tablets.
The reduction of the particle size of clarithromycin to a particle size of D90 less than 50 microns, particularly less than 35 microns results in improved bioavailability of clarithromycin pharmaceutical compositions as compared to clarithromycin pharmaceutical compositions that contain larger sized clarithromycin particles. Clarithromycin particles having a D90 particle size of less than about 50 microns, particularly less than about 35 microns are referred to herein as "micronized clarithromycin particles." As used herein,
"D9o particle size" is the particle size of at least 90% of the particles of clarithromycin used in the composition.
When clarithromycin is micronized, the resulting particles can be difficult to process because micronized particles may possess poor flow properties and have a tendency to agglomerate during processing. To overcome these potential and actual difficulties, the clarithromycin may be micronized in the presence of one or more pharmaceutically inert carrier(s) or mixed with inert carriers after micronization to neutralize the static charge.
As used herein, the term "pharmaceutically inert carrier" refers to a substance that is physiologically acceptable, compatible with the drug and other excipients in the formulation, and has a capacity to adsorb the drug on its surface. Carriers prevent reagglomeration of drug particles and also help in wetting of the drug by uptake of water by capillary action and thereby enhancing drug dissolution further.
The pharmaceutically inert carrier may be selected from cellulose derivatives such as microcrystalline cellulose and carboxymethyl cellulose; silicate derivatives such as magnesium silicate, colloidal silicon dioxide, magnesium trisilicate, and magnesium aluminum silicate; and clays such as veegum, bentonite, etc.
The micronized clarithromycin, either with or without an inert carrier, then is processed with a suitable wetting agent. Wetting agent may be selected from one or more of gelatin, casein, lecithin (phosphatides), glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, polyethylene glycols, polyoxyethylene stearates, sodium dodecylsulfate, partial fatty acid esters of polyhydroxy ethylene sorbitan, such as polyethylene glycol sorbitan monolaurate, monopalmitate, monostearate and monooleate; polyethylene glycol sorbitan tristearate and trioleate (which are obtainable, for example, under the trade name Tween); polyethylene glycol sorbitan monolaurate and monostearate; polyethylene glycol sorbitan monooleate, polyhydroxyethylene fatty alcohol ethers; polyoxyethylene fatty acid esters; ethylene oxide/propylene oxide block copolymers (which are obtainable, for example, under the trade name Pluronic); furthermore sugar ethers and sugar esters; phospholipids and their derivatives; and ethoxylated triglycerides such as the derivatives of castor oil (which are obtainable, for example, under the trade name Cremophor).
The required concentration for the wetting agent in the aqueous or hydroalcoholic wetting solution is an amount required for sufficient wetting. This amount further depends upon whether incremental or single shot wetting treatments are employed. Generally small incremental treatments will require less wetting agent than a larger single shot treatment. In any case, it has been found that satisfactory results are obtained when the amount of wetting agent is from about 0.025% to about 5.0% by weight of clarithromycin.
The processing of micronized clarithromycin with a wetting agent is the most critical step as the solution of wetting agent(s) should only form a layer or film over the micronized clarithromycin particles. Without restricting to any particular theory, it is believed that the wetting agents form a layer or coat over clarithromycin particles which bring about enhancement in wetting characteristics of clarithromycin. This eventually results in increased absorption and bioavailability of clarithromycin.
The micronized clarithromycin particles may be processed by using any of the processes known in the conventional art which may be selected from amongst granulation, particle coating and spray drying.
The wetted clarithromycin particles are dried using conventionally known methods of drying such as spray drying or fluidized bed drying.
The dried particles are milled to break the agglomerates and finally processed to form a solid formulation (e.g., tablet) that includes a rate controlling polymer and one or more pharmaceutically acceptable excipients. The rate controlling polymer provides sustained or extended release characteristics to the finished dosage form such that a patient can reduce the number of times per day that they must take clarithromycin to once or twice per day. For example, the amount of micronized clarithromycin in the finished dosage form can be present at between approximately 100 mg and 1000 mg and the finished dosage form taken only once per day.
The rate-controlling polymers of the solid formulation and finished dosage form may be selected from the group that includes carbohydrate gum, polyuronic acid salts, cellulose ethers, acrylic acid polymers and mixtures, thereof. Carbohydrate gums may be selected
from the group that includes xanthan gum, tragacanth gum, gum karaya, guar gum, acacia, gellan, locust bean gum and other carbohydrate gums having similar properties. Polyuronic acid salts include alkali metal salts of alginic acid or pectic acid and mixtures thereof. Examples of alkali metal salts of alginic acid that may be used include sodium alginate, potassium alginate, ammonium alginate and other suitable alkali metal salts of alginic acid. Cellulose ethers include hydroxypropyl methyl cellulose, hydroxypropyl cellulose and other suitable cellulose ethers. Any suitable polyacrylic acid polymer, such as is available under the brand name carbopol, may be used.
Rate controlling polymers constitute 0.5-4.5% w/w of the tablet.
The other pharmaceutically acceptable excipients include lubricants, binders, fillers and diluents. Lubricants include talc, calcium stearate, magnesium stearate, polyethylene glycols, silicon dioxide, sodium lauryl sulphate, sodium stearyl fumarate, other suitable, known lubricants, and mixtures thereof. Binders include polyvinyl pyrrolidone (PVP) and other suitable, known binders. Fillers and diluents include lactose and other suitable, known fillers and diluents.
According to one of the embodiments, the process comprises:
1. micronization of clarithromycin,
2. processing the micronized clarithromycin with a solution of sufficient amount of
wetting agent,
3. drying the mixture of step 2,
4. milling;
5. blending milled material with polymers and other excipients,
6. granulating;
7. drying the granules, lubricating and compressing to form tablets.
The following examples are provided to illustrate various implementations of the invention and are not intended to limit it.
EXAMPLE 1
Preparation of Extended release Clarithromycin tablets
(Table Removed)
Process:
Polyethylene glycol and polyoxyethylene sorbitan ester were dissolved in a mixture of isopropyl alcohol and purified water (25:75). This solution was slowly added to micronized Clarithromycin particles in a high shear mixer. The wet particles were dried in a fluidized bed dryer at 60°C and milled. The dried and milled Clarithromycin particles, hydroxypropyl methylcellulose, polyvinyl pyrrolidone and lactose were sieved through a British Standard Sieve (BSS) 44 mesh sieve, blended together, and granulated with water. The resulting granulate was dried in a fluid bed drier at 60°C for 20 minutes. The dried granules were sifted through a BSS 16 mesh sieve. The granules obtained were lubricated with the remaining ingredients and compressed to tablets.
EXAMPLE 2
Preparation of Extended release Clarithromycin tablets
(Table Removed)
Process: As followed in Example 1.
The release profile of clarithromycin extended release tablets prepared with untreated clarithromycin particles and clarithromycin particles wetted with wetting agents is provided in Table 1.
Table 1: Release profile of tablets prepared without wetting agents and tablets prepared according to Examples 1 and 2 in pH 6.8 phosphate buffer / 1000ml/USP Apparatus 1/100 rpm
(Table Removed)
As can be seen from the data above that only 13% of clarithromycin is released without wetting agent, whereas when clarithromycin is wetted with wetting agent, a release of about 50 % is obtained.
Pharmacokinetic evaluation
Extended release clarithromycin tablets (1000 mg) prepared without wetting agent were subjected to pharmacokinetic investigation along with Biaxin XL , 2 x 500 mg tablets, currently marketed by Abbott, in normal healthy male subjects under fasting conditions.
Values for pharmacokinetic parameters, including observed Cmax, AUCo-tand AUGo-*, were
calculated using standard non-compartmental methods. The results as indicated by ratio of
test to reference, are shown in Table 2.
Test (A): Clarithromycin XL tablets 1000 mg (without wetting agent)
Reference (R): Biaxin XL (2X 500 mg) tablets
Table 2: Summary of pharmacokinetic parameters
(Table Removed)
A similar study was carried out using extended release tablets prepared according to Examples 1 and 2, in healthy male subjects under fasting conditions.
Values for pharmacokinetic parameters, including observed Cmax, AUCo-tand AUCo-«x, were calculated using standard non-compartmental methods. The results as indicated by ratio of test to reference, are shown in Table 3.
Test (C): Clarithromycin XL 1000 mg tablets of Example 1 Test (D): Clarithromycin XL 1000 mg tablets of Example 2 Reference (R): Biaxin XL (2 X 500 mg) tablets
Table 3: Summary of pharmacokinetic parameters
(Table Removed)
As is evident from the results, the Area Under the Curve is comparable to the test formulation when the Clarithromycin tablets are prepared using a wetting agent.
While several particular forms of the invention have been illustrated and described, it will be apparent that various modifications and combinations of the invention detailed in the text can be made without departing from the spirit and scope of the invention. For example, the Clarithromycin used in the pharmaceutical compositions does not necessarily need to include only micronized Clarithromycin but instead can be made up of a mixture of micronized and unmicronized Clarithromycin, e.g., a first batch of Clarithromycin is micronized and then mixed with a second batch of Clarithromycin which has not been micronized. Moreover, the micronized Clarithromycin may be administered with (e.g., as a single pharmaceutical combination composition, simultaneously, or within a short time) other drugs and drug products to treat conditions that may be related to or occur concurrently with a condition that involves the need to provide antibacterial activity using Clarithromycin. Such drugs that may be co-administered with the micronized Clarithromycin generally include one or more of omeprazole, metronidazole, amoxicillin,
rifampicin, lansoprazole, ciprofloxacin, ethambutol, and ritonavir. For example, the combinations may include a single pharmaceutical composition or joint administration of: (1) omeprazole, metronidazole, and clarithromycin; (2) omeprazole, amoxicillin, and clarithromycin; (3) rifampicin and clarithromycin; (4) lansoprazole and clarithromycin; (5) ciprofloxacin and clarithromycin; (6) lansoprazole, amoxicillin, and clarithromycin; and (7) ethambutol, ritonavir, and clarithromycin.
Further, it is contemplated that any single feature or any combination of optional features of the inventive variations described herein may be specifically excluded from the claimed invention and be so described as a negative limitation. Accordingly, it is not intended that the invention be limited, except as by the appended claims.

WE CLAIM:
1. An extended release clarithromycin tablet comprising micronized
clarithromycin; wherein said micronized clarithromycin has been processed
with a wetting agent.
2. The extended release clarithromycin tablet according to claim 1 wherein
clarithromycin is more than 70% w/w of the tablet.
3. The extended release clarithromycin tablet according to claim 1 wherein
clarithromycin is from about 70% w/w- 90% w/w of the tablet.
4. The extended release tablet of claims 1, wherein the clarithromycin is
between approximately 100 mg and approximately 1000 mg.
5. The extended release tablet of claim 1, wherein micronized clarithromycin
has a particle size less than 50 microns.
6. The extended release tablet of claim 1, wherein micronized clarithromycin
has a particle size less than 35 microns.
7. The extended release tablet of claim 1 wherein wetting agents comprise one
or more of gelatin, casein, lecithin, glycerol monostearate, cetostearyl
alcohol, cetomacrogol emulsifying wax, polyethylene glycols,
polyoxyethylene stearates, sodium dodecylsulfate, partial fatty acid esters of
polyhydroxy ethylene sorbitan, such as polyethylene glycol sorbitan
monolaurate, monopalmitate, monostearate and monooleate; polyethylene
glycol sorbitan tristearate and trioleate; polyethylene glycol sorbitan
monolaurate and monostearate; polyethylene glycol sorbitan monooleate,
polyhydroxyethylene fatty alcohol ethers such as polyoxyethylene cetyl
stearyl ether; corresponding lauryl ethers; polyoxyethylene fatty acid esters;
ethylene oxide/propylene oxide block copolymers; sugar ethers and sugar
esters; phospholipids and their derivatives; and ethoxylated triglycerides
such as the derivatives of castor oil.
8. The extended release tablet of claim 7 wherein the wetting agent is
polyoxyethylene fatty acid ester.
9. The extended release tablet of claim 7 wherein the wetting agent is
ethoxylated derivative of castor oil.
10. The extended release tablet of claim 1, wherein wetting agent is present in
an amount from about 0.025% to about 5% w/w of the tablet.
11. The extended release tablet of claim 1, wherein it further comprises one or
more rate controlling polymers.
12. The extended release tablet of claim 11, wherein the rate controlling
polymers comprises one or more of carbohydrate gums, polyuronic acid
salts, cellulose ethers, and acrylic acid polymers.
13. The extended release tablet of claim 12, wherein the carbohydrate gums
comprise one or more of xanthan gum, tragacanth gum, gum karaya, guar
gum, acacia, gellan, and locust bean gum.
14. The extended release tablet of claim 12, wherein the polyuronic acid salts
comprise one or more of alkali metal salts of alginic acid and pectic acid.
15. The extended release tablet of claim 12, wherein the cellulose ethers
comprise one or more of hydroxypropyl methylcellulose, hydroxypropyl
cellulose, and carboxymethyl cellulose.
16. The extended release tablet of claim 12, wherein the acrylic polymers
comprise the acrylic polymer available under the brand name carbopol.
17. The extended release tablet of claim 11, wherein rate-controlling polymers
constitute 0.5-4.5% w/w of the tablet.
18. The extended release tablet of claim 1, further comprising one or more
pharmaceutically acceptable excipients.
19. The extended release tablet of claims 18, wherein the pharmaceutically
acceptable excipients comprise one or more of lubricants and fillers.
20. The extended release tablet of claim 1, wherein the tablet is administered
once a day.
21. The extended release tablet of claim 1, wherein the clarithromycin is
micronized in air jet mill.
22. The extended release tablet of claim 1, wherein the clarithromycin is co-
micronized with one or more pharmaceutical inert carriers.
23. The extended release tablet of claim 22, wherein the pharmaceutically inert
carrier comprises one or more cellulose derivatives, silicate derivatives, and
clays.
24. The extended release tablet of claim 23, wherein the cellulose derivative
comprises one or more of microcrystalline cellulose and carboxymethyl
cellulose.
25. The extended release tablet of claim 23, wherein the silicate derivative
comprises one or more of magnesium silicate, colloidal silicon dioxide,
magnesium trisilicate, and magnesium aluminium silicate.
26. The extended release tablet of claim 23 wherein clay comprises one or more
of kaolin, veegum and bentonite.
27. The extended release tablet of claim 22, wherein the amount of
pharmaceutically inert carrier is between approximately 2% and
approximately 25% by weight relative to the total weight of the tablet.
28. The extended release tablet of claim 1, wherein the tablet exhibits improved
absorption characteristics relative to a pharmaceutical composition of
clarithromycin without wetting agent.
29. The extended release tablet of claim 1, wherein the tablet exhibits an area-
under-the-curve (ADC) comparable in fed as well as fasting states when
compared with Biaxin XL tablets (extended release tablets; 2 X 500 mg),
marketed by Abbott..
30. The extended release tablet of claim 1, further comprising one or more of
active ingredients, wherein the active ingredients comprise one or more of
omeprazole, metronidazole, amoxicillin, rifampicin, lansoprazole,
ciprofloxacin, ethambutol, and ritonavir.
31. The extended release tablet of claim 30, wherein the clarithromycin and the
one or more active ingredients are combined in a single pharmaceutical
composition.
32. The extended release tablet of claim 1, wherein the pharmaceutical
composition further comprises unmicronized clarithromycin.
33. An extended release tablet comprising a mixture of about 70% to about 90%
by weight of micronized clarithromycin; from about 0.5% to about 4.5% by
weight of rate-controlling polymers; and from about 0.025% to about 5.0% by
weight of a wetting agent.
34. The extended release tablet of claim 33, wherein clarithromycin has a
particle size less than 50 microns.
35. The extended release tablet of claim 33, wherein clarithromycin has a
particle size less than 35 microns.
36. The extended release tablet of claim 33 wherein wetting agents comprise
one or more of gelatin, casein, lecithin, glycerol monostearate, cetostearyl
alcohol, cetomacrogol emulsifying wax, polyethylene glycols,
polyoxyethylene stearates, sodium dodecylsulfate, partial fatty acid esters of
polyhydroxy ethylene sorbitan, such as polyethylene glycol sorbitan
monolaurate, monopalmitate, monostearate and monooleate; polyethylene
glycol sorbitan tristearate and trioleate; polyethylene glycol sorbitan
monolaurate and monostearate; polyethylene glycol sorbitan monooleate,
polyhydroxyethylene fatty alcohol ethers such as polyoxyethylene cetyl
stearyl ether; corresponding lauryl ethers; polyoxyethylene fatty acid esters;
ethylene oxide/propylene oxide block copolymers; sugar ethers and sugar
esters; phospholipids and their derivatives; and ethoxylated triglycerides
such as the derivatives of castor oil.
37. The extended release tablet of claim 36 wherein the wetting agent is
polyoxyethylene fatty acid ester.
38. The extended release tablet of claim 36 wherein the wetting agent is
ethoxylated derivative of castor oil.
39. The extended release tablet of claim 33, wherein the rate controlling
polymers comprises one or more of carbohydrate gums, polyuronic acid
salts, cellulose ethers, and acrylic acid polymers.
40. The extended release tablet of claim 39, wherein the carbohydrate gums
comprise one or more of xanthan gum, tragacanth gum, gum karaya, guar
gum, acacia, gellan, and locust bean gum.
41. The extended release tablet of claim 39, wherein the polyuronic acid salts
comprise one or more of alkali metal salts of alginic acid and pectic acid.
42. The extended release tablet of claim 39, wherein the cellulose ethers
comprise one or more of hydroxypropyl methylcellulose, hydroxypropyl
cellulose, and carboxymethyl cellulose.
43. The extended release tablet of claim 39, wherein the acrylic polymers
comprise the acrylic polymer available under the brand name carbopol.
44. The extended release tablet of claim 33, further comprising one or more
pharmaceutically acceptable excipients.
45. The extended release tablet of claims 44, wherein the pharmaceutically
acceptable excipients comprise one or more of lubricants and fillers.
46. The extended release tablet of claims 33, wherein the tablet is administered
once a day.
47. The extended release tablet of claim 33, wherein the clarithromycin is
micronized in air jet mill.
48. The extended release tablet of claim 33, wherein the clarithromycin is co-
micronized with one or more pharmaceutical inert carriers.
49. The extended release tablet of claim 48, wherein the pharmaceutically inert
carrier comprises one or more cellulose derivatives, silicate derivatives, and
clays.
50. The extended release tablet of claim 49, wherein the cellulose derivative
comprises one or more of microcrystalline cellulose and carboxymethyl
cellulose.
51. The extended release tablet of claim 49, wherein the silicate derivative
comprises one or more of magnesium silicate, colloidal silicon dioxide,
magnesium trisilicate, and magnesium aluminium silicate.
52. The extended release tablet of claim 49 wherein clay comprises one or more
of kaolin, veegum and bentonite.
53. The extended release tablet of claim 48, wherein the amount of
pharmaceutically inert carrier comprises between approximately 2% and
approximately 25% by weight relative to the total weight of the
pharmaceutical composition.
54. The extended release tablet of claim 33, wherein the tablet exhibits improved
absorption characteristics relative to a pharmaceutical composition of
clarithromycin without wetting agent.
55. The extended release tablet of claim 33, wherein the tablet exhibits an area-
under-the-curve (AUC) comparable in fed as well as fasting states when
compared with Biaxin XL tablets (extended release tablets; 2 X 500 mg),
marketed by Abbott..
56. The extended release tablet of claim 33, further comprising one or more of
active ingredients, wherein the active ingredients comprise one or more of
omeprazole, metronidazole, amoxicillin, rifampicin, lansoprazole,
ciprofloxacin, ethambutol, and ritonavir.
57. The extended release tablet of claim 56, wherein the clarithromycin and the
one or more active ingredients are combined in a single pharmaceutical
composition.
58. The extended release tablet of claim 33, wherein the pharmaceutical
composition further comprises unmicronized clarithromycin.
59. A process for preparing an extended release tablet of clarithromycin, the
process comprising:
a. micronizing clarithromycin,
b. processing of clarithromycin with a sufficient amount of solution of
wetting agent,
c. drying the mixture of step b,
d. blending the material of step c with rate-controlling polymers and other
excipients,
e. granulating;
f. drying the granules, lubricating and compressing to form tablets.
60. A process for preparing an extended release tablet of clarithromycin, the
process comprising:
a. micronizing clarithromycin,
b. processing of clarithromycin with a wetting sufficient amount of
solution of wetting agent,
c. drying the mixture of step b,
d. milling,
e. blending milled material with rate-controlling polymers and other
excipients,
f. granulating;
g. drying the granules, lubricating and compressing to form tablets.
61. The process of claims 59-60, wherein the clarithromycin is between
approximately 100 mg and approximately 1000 mg of the tablet.
62. The process of claims 59-60, wherein the clarithromycin is micronized to
have a particle size less than 50 microns.
63. The process of claims 59-60, wherein the clarithromycin is micronized to
have a particle size less than 35 microns.
64. The process of claims 59-60, wherein wetting agents comprise one or more
of gelatin, casein, lecithin, glycerol monostearate, cetostearyl alcohol,
cetomacrogol emulsifying wax, polyethylene glycols, polyoxyethylene
stearates, sodium dodecylsulfate, partial fatty acid esters of polyhydroxy
ethylene sorbitan, such as polyethylene glycol sorbitan monolaurate,
monopalmitate, monostearate and monooleate; polyethylene glycol sorbitan
tristearate and trioleate; polyethylene glycol sorbitan monolaurate and
monostearate; polyethylene glycol sorbitan monooleate, polyhydroxyethylene
fatty alcohol ethers such as polyoxyethylene cetyl stearyl ether;
corresponding lauryl ethers; polyoxyethylene fatty acid esters; ethylene
oxide/propylene oxide block copolymers; sugar ethers and sugar esters;
phospholipids and their derivatives; and ethoxylated triglycerides such as the
derivatives of castor oil.
65. The process of claim 64 wherein the wetting agent is polyoxyethylene fatty
acid ester.
66. The process of claim 64 wherein the wetting agent is ethoxylated derivative
of castor oil.
67. The process of claims 59-60, wherein the rate controlling polymers
comprises one or more of carbohydrate gums, polyuronic acid salts, cellulose
ethers, and acrylic acid polymers.
68. The process of claim 67, wherein the carbohydrate gums comprise one or
more of xanthan gum, tragacanth gum, gum karaya, guar gum, acacia,
gellan, and locust bean gum.
69. The process of claim 67, wherein the polyuronic acid salts comprise one or
more of alkali metal salts of alginic acid and pectic acid.
70. The process of claim 67, wherein the cellulose ethers comprise one or more
of hydroxypropyl methylcellulose, hydroxypropyl cellulose, and
carboxymethyl cellulose.
71. The process of claim 67, wherein the acrylic polymers comprise the acrylic
polymer available under the brand name carbopol.
72. The process of claims 59-60, wherein micronization of clarithromycin is
carried out in an air jet mill.
73. The process of claims 59-60, wherein micronizing comprises co-micronizing
the clarithromycin with one or more pharmaceutically inert carriers.
74. The process of claim 73, wherein the pharmaceutically inert carrier
comprises one or more cellulose derivatives, silicate derivatives, and clays.
75. The process of claim 74, wherein the pharmaceutically inert carrier is
cellulose derivative.
76. An extended release tablet extended release tablets of clarithromycin,
comprising more than 70% w/w of micronized clarithromycin, wherein said
clarithromycin has been processed with a wetting agent.
77. The extended release clarithromycin tablet according to claim 76 wherein
total clarithromycin content is from about 70% w/w-90% w/w.
78. The extended release tablet of claims 76-77, wherein the clarithromycin is
between approximately 100 mg and approximately 1000 mg.
79. The extended release tablet of claims 76-77, wherein clarithromycin has a
particle size less than 50 microns.
80. The extended release tablet of claims 76-77, wherein clarithromycin has a
particle size less than 35 microns.
81. The extended release tablet of claims 76-77 wherein wetting agents
comprise one or more of gelatin, casein, lecithin, glycerol monostearate,
cetostearyl alcohol, cetomacrogol emulsifying wax, polyethylene glycols,
polyoxyethylene stearates, sodium dodecylsulfate, partial fatty acid esters of
polyhydroxy ethylene sorbitan, such as polyethylene glycol sorbitan
monolaurate, monopalmitate, monostearate and monooleate; polyethylene
glycol sorbitan tristearate and trioleate; polyethylene glycol sorbitan
monolaurate and monostearate; polyethylene glycol sorbitan monooleate,
polyhydroxyethylene fatty alcohol ethers such as polyoxyethylene cetyl
stearyl ether; corresponding lauryl ethers; polyoxyethylene fatty acid esters;
ethylene oxide/propylene oxide block copolymers; sugar ethers and sugar
esters; phospholipids and their derivatives; and ethoxylated triglycerides such as the derivatives of castor oil.
82. The extended release tablet of claim 81 wherein the wetting agent is
polyoxyethylene fatty acid ester.
83. The extended release tablet of claim 81 wherein the wetting agent is
ethoxylated derivative of castor oil.
84. The extended release tablet of claims 76-77, wherein wetting agent is
included in an amount from about 0.025% to about 5% w/w of the tablet.
85. The extended release tablets of claims 76-77, further comprising one or more
rate controlling polymers.
86. The extended release tablet of claim 85, wherein the rate controlling
polymers comprises one or more of carbohydrate gums, polyuronic acid
salts, cellulose ethers, and acrylic acid polymers.
87. The extended release tablet of claim 86, wherein the carbohydrate gums
comprise one or more of xanthan gum, tragacanth gum, gum karaya, guar
gum, acacia, gellan, and locust bean gum.
88. The extended release tablet of claim 86, wherein the polyuronic acid salts
comprise one or more of alkali metal salts of alginic acid and pectic acid.
89. The extended release tablet of claim 86, wherein the cellulose ethers
comprise one or more of hydroxypropyl methylcellulose, hydroxypropyl
cellulose, and carboxymethyl cellulose.
90. The extended release tablet of claim 86, wherein the acrylic polymers
comprise the acrylic polymer available under the brand name carbopol.
91. The extended release tablet of claim 85 wherein rate-controlling polymers
constitute 0.5-4.5% w/w of the tablet.
92. The extended release tablet of claims 76-77, further comprising one or more
pharmaceutically acceptable excipients.
93. The extended release tablet of claims 92, wherein the pharmaceutically
acceptable excipients comprise one or more of lubricants and fillers.
94. The extended release tablet of claims 76-77, wherein the clarithromycin is
micronized in air jet mill.
95. The extended release tablet of claims 76-77, wherein the clarithromycin is
co-micronized with one or more pharmaceutical inert carriers.
96. The extended release tablet of claim 95, wherein the pharmaceutically inert
carrier comprises one or more cellulose derivatives, silicate derivatives, and
clays.
97. The extended release tablet of claim 96, wherein the cellulose derivative
comprises one or more of microcrystalline cellulose and carboxymethyl
cellulose.
98. The extended release tablet of claim 96, wherein the silicate derivative
comprises one or more of magnesium silicate, colloidal silicon dioxide,
magnesium trisilicate, and magnesium aluminium silicate.
99. The extended release tablet of claim 96, wherein clay comprises one or more
of kaolin, veegum and bentonite.
100. The extended release tablet of claim 95, wherein the amount of
pharmaceutically inert carrier comprises between approximately 2% and
approximately 25% by weight relative to the total weight of the
pharmaceutical composition.
101. The extended release tablet of claims 76-77, wherein the tablet is
administered once a day.
102. The extended release tablet of claims 76-77, wherein the tablet exhibits
improved absorption characteristics relative to a pharmaceutical composition
of clarithromycin without wetting agent.
103. The extended release tablet of claims 76-77, wherein the tablet exhibits an
area-under-the-curve (AUC) comparable in fed as well as fasting states when
compared with Biaxin XL tablets (extended release tablets; 2 X 500 mg),
marketed by Abbott..
104. The extended release tablet of claims 76-77, further comprising one or more
of active ingredients, wherein the active ingredients comprise one or more of
omeprazole, metronidazole, amoxicillin, rifampicin, lansoprazole,
ciprofloxacin, ethambutol, and ritonavir.
105. The extended release tablet of claim 104, wherein the clarithromycin and the
one or more active ingredients are combined in a single pharmaceutical
composition.
106. The extended release tablet of claims 76-77, wherein the pharmaceutical
composition further comprises unmicronized clarithromycin.
107. An extended release clarithromycin tablet of 1000 mg strength, wherein total
weight of the tablet does not exceed 1400 mg and wherein said
clarithromycin has been processed with a wetting agent.
108. The extended release tablet of claim 107, wherein clarithromycin has a
particle size less than 50 microns.
109. The extended release tablet of claim 107, wherein clarithromycin has a
particle size less than 35 microns.
110. The extended release tablet of claim 107 wherein wetting agents comprise
one or more of gelatin, casein, lecithin, glycerol monostearate, cetostearyl
alcohol, cetomacrogol emulsifying wax, polyethylene glycols,
polyoxyethylene stearates, sodium dodecylsulfate, partial fatty acid esters of
polyhydroxy ethylene sorbitan, such as polyethylene glycol sorbitan
monolaurate, monopalmitate, monostearate and monooleate; polyethylene
glycol sorbitan tristearate and trioleate; polyethylene glycol sorbitan
monolaurate and monostearate; polyethylene glycol sorbitan monooleate,
polyhydroxyethylene fatty alcohol ethers such as polyoxyethylene cetyl
stearyl ether; corresponding lauryl ethers; polyoxyethylene fatty acid esters;
ethylene oxide/propylene oxide block copolymers; sugar ethers and sugar
esters; phospholipids and their derivatives; and ethoxylated triglycerides
such as the derivatives of castor oil.
111. The extended release tablet of claim 110 wherein the wetting agent is
polyoxyethylene fatty acid ester.
112. The extended release tablet of claim 110 wherein the wetting agent is
ethoxylated derivative of castor oil.
113. The extended release tablet of claim 107, wherein wetting agent is included
in an amount from about 0.025% to about 5% w/w of the tablet.
114. The extended release tablet of claim 107, further comprising one or more
rate controlling polymers.
115. The extended release tablet of claim 114, wherein the rate controlling
polymers comprises one or more of carbohydrate gums, polyuronic acid
salts, cellulose ethers, and acrylic acid polymers.
116. The extended release tablet of claim 115, wherein the carbohydrate gums
comprise one or more of xanthan gum, tragacanth gum, gum karaya, guar
gum, acacia, gellan, and locust bean gum.
117. The extended release tablet of claim 115, wherein the polyuronic acid salts
comprise one or more of alkali metal salts of alginic acid and pectic acid.
118. The extended release tablet of claim 115, wherein the cellulose ethers
comprise one or more of hydroxypropyl methylcellulose, hydroxypropyl
cellulose, and carboxymethyl cellulose.
119. The extended release tablet of claim 115, wherein the acrylic polymers
comprise the acrylic polymer available under the brand name carbopol.
120. The extended release tablet of claim 114 wherein rate-controlling polymers
constitute 0.5-4.5% w/w of the tablet.
121. The extended release tablet of claim 107 further comprising one or more
pharmaceutically acceptable excipients.
122. The extended release tablet of claims 121, wherein the pharmaceutically
acceptable excipients comprise one or more of lubricants and fillers.
123. The extended release tablet of claim 107, wherein the clarithromycin is
micronized in air jet mill.
124. The extended release tablet of claim 107, wherein the clarithromycin is co-
micronized with one or more pharmaceutical inert carriers.
125. The extended release tablet of claim 124, wherein the pharmaceutically'inert
carrier comprises one or more cellulose derivatives, silicate derivatives, and
clays.
126. The extended release tablet of claim 125, wherein the cellulose derivative
comprises one or more of microcrystalline cellulose and carboxymethyl
cellulose.
127. The extended release tablet of claim 125, wherein the silicate derivative
comprises one or more of magnesium silicate, colloidal silicon dioxide,
magnesium trisilicate, and magnesium aluminium silicate.
128. The extended release tablet of claim 125 wherein clay comprises one or
more of kaolin, veegum and bentonite.
129. The extended release tablet of claim 124, wherein the amount of
pharmaceutically inert carrier comprises between approximately 2% and
approximately 25% by weight relative to the total weight of the pharmaceutical composition.
130. The extended release tablet of claim 107, wherein the tablet is administered
once a day.
131. The extended release tablet of claim 107, wherein the tablet exhibits
improved absorption characteristics relative to a pharmaceutical composition
of clarithromycin without wetting agent.
132. The extended release tablet of claim 107, wherein the tablet exhibits an area-
under-the-curve (AUC) comparable in fed as well as fasting states when
compared with Biaxin XL tablets (extended release tablets; 2 X 500 mg),
marketed by Abbott..
133. The extended release tablet of claim 107, further comprising one or more of
active ingredients, wherein the active ingredients comprise one or more of
omeprazole, metronidazole, amoxicillin, rifampicin, lansoprazole,
ciprofloxacin, ethambutol, and ritonavir.
134. The extended release tablet of claim 133, wherein the clarithromycin and the
one or more active ingredients are combined in a single pharmaceutical
composition.
135. The extended release tablet of claim 107, wherein the pharmaceutical
composition further comprises unmicronized clarithromycin.
136. A method of providing antibacterial activity to a mammal in need of
treatment, the method comprising administering a pharmaceutical
composition comprising micronized clarithromycin and one or more
pharmaceutically acceptable excipients; wherein said clarithromycin has
been processed with a wetting agent.