U.S. patent application number 17/180443 was filed with the patent office on 2022-02-03 for modified release doxycycline composition.
The applicant listed for this patent is GALDERMA HOLDING SA. Invention is credited to Ankit BAHETI, Bijay Kumar PADHI, Rajeev Singh RAGHUVANSHI.
Application Number | 20220031714 17/180443 |
Document ID | / |
Family ID | |
Filed Date | 2022-02-03 |
United States Patent
Application |
20220031714 |
Kind Code |
A1 |
BAHETI; Ankit ; et
al. |
February 3, 2022 |
MODIFIED RELEASE DOXYCYCLINE COMPOSITION
Abstract
Doxycycline formulations with a reduced food effect are
disclosed. Particularly disclosed are modified release formulations
which can be administered once a day and exhibit a reduced food
effect. Methods of treating inflammatory conductions such as
rosacea or inflammatory symptoms such as the papules and pustules
of rosacea or acne vulgaris are also disclosed.
Inventors: |
BAHETI; Ankit; (Indore,
IN) ; PADHI; Bijay Kumar; (Ganjam District, IN)
; RAGHUVANSHI; Rajeev Singh; (Gurgaon, IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
GALDERMA HOLDING SA |
La Tour-de-Peilz |
|
CH |
|
|
Appl. No.: |
17/180443 |
Filed: |
February 19, 2021 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
16388415 |
Apr 18, 2019 |
10953022 |
|
|
17180443 |
|
|
|
|
15875369 |
Jan 19, 2018 |
10300081 |
|
|
16388415 |
|
|
|
|
15359292 |
Nov 22, 2016 |
9901588 |
|
|
15875369 |
|
|
|
|
14946715 |
Nov 19, 2015 |
9532996 |
|
|
15359292 |
|
|
|
|
International
Class: |
A61K 31/65 20060101
A61K031/65; A61K 9/00 20060101 A61K009/00; A61K 9/50 20060101
A61K009/50; A61K 9/48 20060101 A61K009/48 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 19, 2014 |
IN |
5805/CHE/2014 |
Claims
1-11. (canceled)
12. A method of treating inflammatory rosacea or an inflammatory
symptom of either rosacea or acne vulgaris comprising administering
to a human patient in need thereof a modified release oral
composition comprising: (i) about 30 to less than about 50 mg of
doxycycline, based on the equivalent weight of doxycycline base,
wherein the doxycycline is in an amount of about 15-20% w/w; (ii)
about 10-18% w/w of one or more water soluble and insoluble
polymers; and (iii) about 1-20% w/w of one or more pharmaceutically
acceptable excipients; wherein the composition is free of any
immediate release component; and wherein the composition provides
at least one of the following pharmacokinetic parameters: (a)
average input rate of about 4 ng/hr/mL to about 15 ng/hr/mL during
a time period of T.sub.0 min to T.sub.30 min, and (b) average input
rate of about 15 ng/hr/mL to about 40 ng/hr/mL during a time period
of T.sub.0 min to T.sub.60 min.
13. The method according to claim 12, wherein the doxycycline is an
acid addition salt of doxycycline.
14. The method according to claim 13, wherein the acid addition
salt of doxycycline is doxycycline hyclate.
15. The method according to claim 14, wherein the doxycycline
hyclate is present in an amount of about 46 mg.
16. The method according to claim 12, wherein the composition
exhibits a reduced food effect selected from the group consisting
of an AUC of less than about 15% and a C.sub.max of less than about
40% upon oral administration to a human.
17. The method according to claim 16, wherein the composition
exhibits a reduced food effect as a C.sub.max of less than about
35% upon oral administration to a human.
18. The method according to claim 12, wherein the composition
provides a reduced food effect whereby both AUC and a C.sub.max are
lower than the food effect of commercially available 40 mg
doxycycline compositions by at least about 15%.
19. The method according to claim 12, where the composition upon
oral administration in a fasting state exhibits bioequivalence to a
commercially available 40 mg doxycycline composition and wherein
the bioequivalence is established by: (a) a 90% Confidence Interval
for mean AUC.sub.(0-t), which is between 80% and 125%, (b) a 90%
Confidence Interval for mean AUC.sub.(0-.infin.), which is between
80% and 125%, and (c) a 90% Confidence Interval for mean C.sub.max,
which is between 80% and 125%.
20. The method according to claim 12, wherein the doxycycline is
present in an amount of about 30 to about 45 mg, based on the
equivalent weight of doxycycline base.
21. The method according to claim 12, wherein the doxycycline is
present in an amount of about 35 to about 45 mg, based on the
equivalent weight of doxycycline base.
22. The method according to claim 12, wherein the inflammatory
symptom of either rosacea or acne vulgaris is papules and pustules
of either rosacea or acne vulgaris.
23. The method according to claim 12, for the treatment of
inflammatory rosacea or an inflammatory symptom of rosacea.
24. The method according to claim 12, wherein the composition
provides a pharmacokinetic parameter of an average input rate of
about 5 ng/hr/mL to about 8 ng/hr/mL during a time period of
T.sub.0 min to T.sub.30 min.
25. The method according to claim 12, wherein the composition
provides a pharmacokinetic parameter of an average input rate of
about 15 ng/hr/mL to about 20 ng/hr/mL during a time period of
T.sub.0 min to T.sub.60 min.
26. The method according to claim 12, wherein wherein the
composition has a dC/dT value of less than about 80% of the dC/dT
value provided by the commercially available 40 mg doxycycline
composition, measured in a single dose human pharmacokinetic study
in a fasting state and in a time period of T.sub.0 min to T.sub.60
mins.
27. The method according to claim 26, wherein the composition has a
dC/dT value of less than about 40% of the dC/dT value provided by
the commercially available 40 mg doxycycline composition.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a Continuation Application of
U.S. patent application Ser. No. 16/388,415, filed Apr. 18, 2019,
which is a Divisional Application of U.S. patent application Ser.
No. 15/875,369, filed Jan. 19, 2018, now U.S. Pat. No. 10,300,081,
which is a Continuation Application of U.S. patent application Ser.
No. 15/359,292, filed Nov. 22, 2016, now U.S. Pat. No. 9,901,588,
which is a Continuation Application of U.S. patent application Ser.
No. 14/946,715, filed Nov. 19, 2015, now U.S. Pat. No. 9,532,996,
which claims the benefit of the filing date of Indian Patent
Application No. IN 5805/CHE/2014, filed Nov. 19, 2014, the
disclosures of which are hereby incorporated herein by
reference.
FIELD OF INVENTION
[0002] The present application relates to a modified release
composition of doxycycline.
BACKGROUND
[0003] Doxycycline is a broad spectrum bacteriostatic compound that
is effective against Gram-positive, Gram-negative, aerobic and
anaerobic bacteria, as well as spirochetes, mycoplasmas,
rickettsiae, chlamydiae and some protozoans. It works by inhibiting
protein synthesis in bacteria or protozoans. It is commonly used in
the treatment of bacterial infections caused by these organisms,
such as urinary tract infections, upper respiratory tract
infections, acne, gonorrhea, chlamydia, anthrax, lyme disease and
others.
[0004] Besides antibiotic activity, doxycycline also has some other
mechanism of actions like interfering with the chemotaxis of
polymorphonuclear leukocytes (PMN) into the inflammatory lesion,
inhibition of PMN derived collagenase, scavenging reactive
oxidative species produced by resident inflammatory cells etc.
Therefore doxycycline is also being used as an anti-inflammatory to
treat inflammatory conditions or symptoms, such as diseases like
periodontitis, rosacea and acne. In these instances, it is used in
an anti-inflammatory effective amount which, may be lower than
traditionally prescribed when doxycycline is used for its
antibiotic activity.
[0005] Doxycycline as an antibiotic is available in 50 mg, 100 mg,
and 200 mg oral doses, whereas as for treating periodontitis and
rosacea, lower strengths of 20 mg & 40 mg oral doses are
marketed as PERIOSTAT.RTM. and ORACEA.RTM. respectively. These
doses can be given once or more per day as directed by a physician.
ORACEA.RTM. is a 40 mg dose administered once in a 24 hour period.
Sustained release formulations of doxycycline are also described in
U.S. Pat. Nos. 5,084,287 and 5,188,836.
[0006] Oral administration of drugs is frequently affected by
food-drug interactions, a phenomenon often described by the term
"food effect". Food effect generally refers to all type of
interactions of food with drug which affect its dissolution,
absorption, distribution, metabolism and/or elimination. The
implications of food effect can, in some instances, include changes
in bioavailability, rate of on-set of therapeutic action, duration
of therapeutic effect and incidence of side effects.
[0007] The food effect is an important issue during the development
of a drug. In some cases food-drug interactions lead to an increase
of drug absorption and the drug formulation may be recommended to
be taken with food in order to be sufficiently absorbed and exert
its expected clinical effect. In some other case food interrupts
the absorption of active agent and therefore it reduces C.sub.max
and AUC leading to poor therapeutic effect. In those cases, there
may be warnings provided to the user to take the drug, for example,
one hour before or two hours after eating.
[0008] The food effect on doxycycline pharmacokinetics is well
known. Indeed, ORACEA.RTM. is reported to have 45% and 22% in
C.sub.max and AUC respectively (meaning that the C.sub.max and AUC
of ORACEA.RTM. when given in the fed versus fasted state differ by
45% and 22% respectively) and carries the exact dosing restriction
noted above.
[0009] In addition to its known impact on the gastrointestinal
microbiology of a patient, doxycycline is known to have possible
adverse gastrological effects which are attributed to irritation of
the mucosa. Such effects may include anorexia, nausea, diarrhoea,
glossitis, dysphagia, enterocolitis. Further there is huge risk of
esophageal irritation and ulceration in patients receiving capsule
and tablet forms of the doxycycline, especially when patients
immediately go to bed or lie down following dosing, or when the
doses are taken without sufficient liquid. Therefore it is
necessary the patients should be administered with adequate amounts
of fluid or food and the patients are instructed to remain sitting
or standing for up to 2 hours post administration to prevent the
possible development of oesophageal irritation. Similar
restrictions are known for other drug products, like
bisphosphonates. These dosing restrictions can understandably cause
inconvenience and discomfort to the patients which can impact
compliance.
[0010] Thus, a need exists to provide a modified release dosage
form of doxycycline with reduced or no significant food effect.
Further it is desired to have a dosage form of doxycycline which
are expected to reduce or prevent risk of esophageal irritation and
ulceration in patients and further improves the compliance.
SUMMARY OF THE INVENTION
[0011] The present application relates to a modified release
composition of doxycycline.
[0012] In one embodiment, the present application relates to a
modified release composition comprising: [0013] I. doxycycline;
[0014] II. one or more water soluble and insoluble polymers; and
[0015] III. one or more pharmaceutically acceptable excipients;
[0016] wherein said composition when subjected to a changeover
dissolution study releases no more than 30% in 30 minutes, in 750
ml of pH 1.2 acidic solution (0.1N HCl); and has at least one of
the following release profile in 950 ml of an pH 6.0 phosphate
buffer solution: [0017] a. less than about 30% in 35 minutes;
[0018] b. less than about 60% in 45 minutes; and [0019] c. more
than 85% in 60 minutes
[0020] In another embodiment, the modified release composition of
the present application comprising doxycycline, wherein said
composition provides at least one of the following pharmacokinetic
parameters: [0021] a. doxycycline plasma concentration of not more
than about 50 ng/ml of doxycycline at 30 minutes; [0022] b.
doxycycline plasma concentration of not more than about 100 ng/ml
of doxycycline at 45 minutes; and [0023] c. doxycycline plasma
concentration of not more than about 200 ng/ml of doxycycline at 60
minutes.
[0024] In another embodiment, the modified release composition of
the present application provides peak plasma concentration from
about 200 ng/ml to about 1000 ng/ml of doxycycline at 90
minutes.
[0025] In another embodiment, the modified release composition of
the present application comprising doxycycline provides at least
one of the following pharmacokinetic parameters: [0026] a.
doxycycline plasma concentration of not more than about 15 ng/ml of
doxycycline at 30 minutes; [0027] b. doxycycline plasma
concentration of not more than about 60 ng/ml of doxycycline at 45
minutes; and [0028] c. doxycycline plasma concentration of not more
than about 200 ng/ml of doxycycline at 60 minutes.
[0029] In another embodiment, the present application relates to a
modified release composition for once daily oral administration
comprising: [0030] I. doxycycline, [0031] II. one or more water
soluble and insoluble polymers and [0032] III. one or more
pharmaceutically acceptable excipients, [0033] wherein said
composition upon oral administration to a human subjects in fasting
state provides at least one of the doxycycline plasma concentration
parameters: [0034] a. not more than about 15 ng/ml of doxycycline
at 30 minutes; [0035] b. not more than about 60 ng/ml of
doxycycline at 45 minutes; and [0036] c. not more than about 200
ng/ml of doxycycline at 60 minutes.
[0037] In another embodiment, the present application relates to a
modified release composition comprising: [0038] I. doxycycline;
[0039] II. one or more water soluble and insoluble polymers; and
[0040] III. one or more pharmaceutically acceptable excipients;
[0041] wherein said composition upon oral administration in fasting
state exhibits bioequivalence to a commercially available 40 mg
doxycycline composition and said bioequivalence is established by:
[0042] a. a 90% Confidence Interval for mean AUC.sub.(0-t), which
is between 80% and 125%, [0043] b. a 90% Confidence Interval for
mean AUC.sub.(0-inf), which is between 80% and 125%, and [0044] c.
a 90% Confidence Interval for mean C.sub.max, which is between 80%
and 125%.
[0045] In another embodiment, the present application relates to a
modified release composition comprising: [0046] I. doxycycline,
[0047] II. one or more water soluble and insoluble polymers and
[0048] III. one or more pharmaceutically acceptable excipients,
[0049] wherein said composition upon oral administration in a fed
state exhibits bioequivalence to a commercially available 40 mg
doxycycline composition administered in fasting state and said
bioequivalence is established by: [0050] a. a 90% Confidence
Interval for mean AUC.sub.(0-t), which is between 80% and 125%; and
[0051] b. a 90% Confidence Interval for mean AUC.sub.(0-inf), which
is between 80% and 125%. In another aspect of this embodiment the
composition is provided as a once a day oral dosage form.
[0052] In another embodiment, the present application relates to a
modified release composition comprising: [0053] I. doxycycline;
[0054] II. one or more water soluble and insoluble polymers; and
[0055] III. one or more pharmaceutically acceptable excipients;
[0056] wherein said composition provides at least one of the
following pharmacokinetic parameters: [0057] a) a fed/fasted ratio
for C.sub.max in the range of about 0.60 to about 1.00; [0058] b) a
fed/fasted ratio for AUC.sub.0-t in the range of about 0.89 to
about 1.00; and [0059] c) a fed/fasted ratio for AUC.sub.0-inf in
the range of about 0.89 to about 1.00.
[0060] In another embodiment, the present application relates to a
method of treating rosacea in a human subject in need thereof
comprising: [0061] I. doxycycline, [0062] II. one or more water
soluble and insoluble polymers, and [0063] III. one or more
pharmaceutically acceptable excipients; [0064] wherein said
composition has reduced food effect.
[0065] In another embodiment, the present application relates to a
method of treating rosacea or an inflammatory symptom of rosacea or
acne vulgaris in a human subject in need thereof comprising: [0066]
I. doxycycline, [0067] II. one or more water soluble and insoluble
polymers and [0068] III. one or more pharmaceutically acceptable
excipients, [0069] wherein said composition upon oral
administration in a fed state exhibits bioequivalence to a
commercially available 40 mg doxycycline composition administered
in fasting state and said bioequivalence is established by: [0070]
a. a 90% Confidence Interval for mean AUC.sub.(0-t), which is
between 80% and 125%; and [0071] b. a 90% Confidence Interval for
mean AUC.sub.(0-inf), which is between 80% and 125%.
[0072] In another embodiment, the method of treating rosacea or an
inflammatory symptom of rosacea or acne vulgaris in a human subject
in need thereof comprising orally administering a modified release
composition of doxycycline, wherein said composition has reduced
food effect.
[0073] In another embodiment, the method of treating rosacea or an
inflammatory symptom of acne vulgaris in a human subject in need
thereof comprising orally administering a modified release
composition of doxycycline, wherein said composition has reduced
food effect, and said food effect is less than about 40% in
C.sub.max
[0074] In another embodiment, the method of treating rosacea or an
inflammatory symptom of rosacea or acne vulgaris in a human subject
in need thereof comprising orally administering a modified release
composition of doxycycline, wherein said composition has reduced
food effect, and said food effect is less than about 35% in
C.sub.max
[0075] In another embodiment, the method of treating rosacea or an
inflammatory symptom of rosacea or acne vulgaris in a human subject
in need thereof comprising orally administering a modified release
composition of doxycycline, wherein said composition has reduced
food effect, and said food effect is less than about 15% in AUC
(AUC.sub.(0-t) and/or AUC.sub.(0-inf)).
[0076] In another embodiment, the method of treating rosacea or an
inflammatory symptom of rosacea or acne vulgaris in a human subject
in need thereof comprising orally administering a modified release
composition of doxycycline, wherein said composition has reduced
food effect, and said food effect is less than about 12% in AUC
(AUC.sub.(0-t) and/or AUC.sub.(0-inf).
[0077] In another embodiment, the method of treating rosacea or an
inflammatory symptom of rosacea or acne vulgaris in a human subject
in need thereof comprising orally administering an once daily
modified release composition comprising doxycycline, wherein said
composition has reduced food effect and said food effect is lower
than the food effect of commercially available 40 mg doxycycline
composition by at least 15% in C.sub.max and AUC (AUC.sub.(0-t)
and/or AUC.sub.(0-inf))
[0078] In another embodiment, the method of treating rosacea or an
inflammatory symptom of rosacea or acne vulgaris in a human subject
in need thereof comprising orally administering a modified release
composition comprising: [0079] I. doxycycline [0080] II. one or
more water soluble and insoluble polymers; and [0081] III. one or
more pharmaceutically acceptable excipients; [0082] wherein said
composition provides at least one of the following pharmacokinetic
parameters: [0083] a) a fed/fasted ratio for C.sub.max in the range
of about 0.60 to about 1.00; [0084] b) a fed/fasted ratio for
AUC.sub.0-t in the range of about 0.89 to about 1.00; and [0085] c)
a fed/fasted ratio for AUC.sub.0-inf in the range of about 0.89 to
about 1.00.
[0086] In another embodiment, the method of treating rosacea or an
inflammatory symptom of rosacea or acne vulgaris in a human subject
in need thereof comprising orally administering a modified release
composition comprising: [0087] I. doxycycline; [0088] II. one or
more water soluble and insoluble polymers; and [0089] III. one or
more pharmaceutically acceptable excipients; [0090] wherein said
composition upon oral administration in fasting state exhibits
bioequivalence to a commercially available 40 mg doxycycline
composition and said bioequivalence is established by: [0091] a. a
90% Confidence Interval for mean AUC.sub.(0-t), which is between
80% and 125%, [0092] b. a 90% Confidence Interval for mean
AUC.sub.(0-inf), which is between 80% and 125%, and [0093] c. a 90%
Confidence Interval for mean C.sub.max, which is between 80% and
125%.
[0094] In another embodiment, the method of treating rosacea or an
inflammatory symptom of rosacea or acne vulgaris in a human subject
in need thereof comprising orally administering a modified release
composition comprising: [0095] I. about 46 mg of doxycycline
hyclate; [0096] II. one or more water soluble and insoluble
polymers; and [0097] III. one or more pharmaceutically acceptable
excipients; [0098] wherein said composition upon oral
administration in fasting state exhibits bioequivalence to a
commercially available 40 mg doxycycline composition and said
bioequivalence is established by:
[0099] d. a 90% Confidence Interval for mean AUC.sub.(0-t), which
is between 80% and 125%, [0100] e. a 90% Confidence Interval for
mean AUC.sub.(0-inf), which is between 80% and 125%, and [0101] f.
a 90% Confidence Interval for mean C.sub.max, which is between 80%
and 125%.
[0102] In another embodiment, the present application relates to a
modified release composition comprising [0103] I. doxycycline;
[0104] II. one or more water soluble and insoluble polymers; and
[0105] III. one or more pharmaceutically acceptable excipients;
[0106] wherein said composition has dC/dT value less than about 80%
of the dC/dT value provided by the commercially available 40 mg
doxycycline composition, and said dC/dT value is measured in a
single dose human pharmacokinetic study in a fasting state and for
a time period of T.sub.0min to T.sub.60mins.
[0107] In another embodiment, the modified release composition of
the present application comprising [0108] I. doxycycline [0109] II.
one or more water soluble and insoluble polymers; and [0110] III.
one or more pharmaceutically acceptable excipients; [0111] wherein
said composition has dC/dTvalue less than about 80% of the dC/dT
value provided by the commercially available 40 mg doxycycline
composition, and said dC/dT value is measured in a single dose
human pharmacokinetic study in a fasting state and in a time period
of T.sub.0min to T.sub.60min, wherein said composition provides at
least one of the following pharmacokinetic parameters: [0112] a.
average input rate of from about 4 ng/hr/ml to about 15 ng/hr/ml
during the time period of T.sub.0min to T.sub.30mins. [0113] b.
average input rate of from about 15 ng/hr/ml to about 40 ng/hr/ml
during the time period of T.sub.0min to T.sub.60mins.
[0114] In another embodiment, the modified release composition of
the present application comprising [0115] I. doxycycline; [0116]
II. one or more water soluble and insoluble polymers; and [0117]
III. one or more pharmaceutically acceptable excipients; [0118]
wherein said composition has dC/dTvalue less than about 80% of the
dC/dT value provided by the commercially available 40 mg
doxycycline composition, and said dC/dT value is measured in a
single dose human pharmacokinetic study in a fasting state and in a
time period of T.sub.0min to T.sub.60min, wherein said composition
provides at least one of the following pharmacokinetic parameters:
[0119] a. average input rate of from about 5 ng/hr/ml to about 8
ng/hr/ml during the time period of T.sub.0min to T.sub.30mins.
[0120] b. average input rate of from about 15 ng/hr/ml to about 20
ng/hr/ml during the time period of T.sub.0min to T.sub.60mins.
[0121] In another embodiment, the modified release composition
comprising [0122] I. doxycycline; [0123] II. one or more water
soluble and insoluble polymers; and [0124] III. one or more
pharmaceutically acceptable excipients; [0125] wherein said
composition has dC/dT value less than about 80% of the dC/dT value
provided by the commercially available 40 mg doxycycline
composition, and said dC/dT value is measured in a single dose
human pharmacokinetic study in a fasting state and in a time period
of T.sub.0min to T.sub.60min, wherein said composition has reduced
food effect.
[0126] In another embodiment, the modified release composition
comprising doxycycline has reduced food effect, and said food
effect is less than about 40% in C.sub.max.
[0127] In another embodiment, the modified release composition of
the present application has reduced food effect, and said food
effect is less than about 35% in C.sub.max.
[0128] In another embodiment, the modified release composition
comprising doxycycline has reduced food effect, and said food
effect is less than about 15% in AUC.sub.(0-t).
[0129] In another embodiment, the modified release composition
comprising doxycycline has reduced food effect, and said food
effect is less than about 12% in AUC.sub.(0-t).
[0130] In another embodiment, the modified release composition
comprising doxycycline has reduced food effect, and said food
effect is less than about 15% in AUC.sub.(0-inf).
[0131] In another embodiment, the modified release composition
comprising doxycycline has reduced food effect, and said food
effect is less than about 12% in AUC.sub.(0-inf).
[0132] In another embodiment, the modified release composition
comprising [0133] I. doxycycline; [0134] II. one or more water
soluble and insoluble polymers; and [0135] III. one or more
pharmaceutically acceptable excipients; [0136] wherein said
composition has dC/dT value less than about 80% of the dC/dT value
provided by the commercially available 40 mg doxycycline
composition, and said dC/dT value is measured in a single dose
human pharmacokinetic study in a fasting state and in a time period
of T.sub.0min to T.sub.60min; and [0137] wherein said composition
has reduced food effect and said food effect is lower than the food
effect of commercially available 40 mg doxycycline composition by
at least 15% in C.sub.max and AUC (AUC.sub.(0-t) and/or
AUC.sub.(0-inf).
[0138] In another embodiment, the modified release composition
comprising [0139] I. doxycycline; [0140] II. one or more water
soluble and insoluble polymers; and [0141] III. one or more
pharmaceutically acceptable excipients; [0142] wherein said
composition has dC/dT value less than about 80% of the dC/dT value
provided by the commercially available 40 mg doxycycline
composition, and said dC/dT value is measured in a single dose
human pharmacokinetic study in a fasting state and in a time period
of T.sub.0min to T.sub.60mins; and [0143] wherein said composition
provides at least one of the following pharmacokinetic parameters:
[0144] a) a fed/fasted ratio for C.sub.max in the range of about
0.60 to about 1.00; [0145] b) a fed/fasted ratio for AUC.sub.0-t in
the range of about 0.89 to about 1.00; and [0146] c) a fed/fasted
ratio for AUC.sub.0-inf in the range of about 0.89 to about
1.00.
[0147] In another embodiment, the modified release composition
comprising [0148] I. doxycycline; [0149] II. one or more water
soluble and insoluble polymers; and [0150] III. one or more
pharmaceutically acceptable excipients; [0151] wherein said
composition has dC/dT value less than 80% of the dC/dT value
provided by the commercially available 40 mg doxycycline
composition, and said dC/dT value is measured in a single dose
human pharmacokinetic study in a fasting state and in a time period
of T.sub.0min to T.sub.60mins; and [0152] wherein said composition
upon oral administration in fasting state exhibits bioequivalence
to a commercially available 40 mg doxycycline composition and said
bioequivalence is established by: [0153] a. a 90% Confidence
Interval for mean AUC.sub.(0-t), which is between 80% and 125%,
[0154] b. a 90% Confidence Interval for mean AUC.sub.(0-inf), which
is between 80% and 125%, and [0155] c. a 90% Confidence Interval
for mean C.sub.max, which is between 80% and 125%.
[0156] In another embodiment, the modified release composition of
the present application is orally administered once daily.
[0157] In another embodiment, the modified release composition of
the present application is orally administered twice daily.
[0158] In another embodiment, the modified release composition of
the present application is orally administered to human subjects in
need thereof.
[0159] In another embodiment, the modified release composition of
the present application comprises doxycycline, wherein said
doxycyline is an acid addition salt of doxycycline. In still
another aspect of this embodiment, the doxycycline is administered
in an amount of between about 30 and less than 50 mg, based on the
weight of doxycycline base, in yet another aspect, between about 35
and about 45 mg, and in yet a further aspect between about 35 and
about 40 mg of doxycycline based on the equivalent weight of
doxycycline base.
[0160] In another embodiment, the modified release composition of
the present application comprises doxycycline, which is doxycycline
hyclate.
[0161] In another embodiment, doxycycline hyclate is present in an
amount of about 46 mg.
[0162] In another embodiment, doxycycline hyclate is present in an
amount of 46.16 mg.
[0163] In another embodiment there is provided a method of treating
inflammatory rosacea or an inflammatory symptom of either rosacea
or acne vulgaris in a human patient in need thereof comprising:
administering to said patient a total daily dose of about 35 mg to
about 45 mg of a doxycycline hydrate or acid addition salt, based
on the equivalent weight of doxycycline base, wherein the total
daily dose of doxycycline is provided so as to result in a reduced
food effect.
[0164] In another aspect of this method the total daily dose is
administered once a day and provides a reduced food effect whereby
both AUC and a C.sub.max are lower than the food effect of
commerically available 40 mg doxycycline compositions by at least
about 15%.
[0165] In another aspect of the method, the total daily dose is
administered once a day less than one hour before or less than two
hours after a meal.
[0166] In another aspect of the method, the total daily dose
exhibits a reduced food effect selected from the group consisting
of an AUC of less than about 15% and a C.sub.max of less than about
40% upon oral administration to a human in a fed state.
[0167] In another aspect of the method, upon oral administration in
a fasting state the total daily dose exhibits bioequivalence to a
commercially available 40 mg doxycycline composition.
[0168] In another aspect of the method, bioequivalence is
established by: [0169] a. a 90% Confidence Interval for mean
AUC.sub.(0-t), which is between 80% and 125%, [0170] b. a 90%
Confidence Interval for mean AUC.sub.(0-.infin.), which is between
80% and 125%, and [0171] c. a 90% Confidence Interval for mean
C.sub.max, which is between 80% and 125%.
[0172] In another aspect of the method, the acid addition salt is
doxycycline hyclate is present in an amount of about 46 mg.
[0173] In another aspect of the method, the doxycycline is a
hydrate and the hydrate is the monohydrate.
[0174] In another aspect of the method, the inflammatory symptom of
either rosacea or acne vulgaris is papules and pustules of either
rosacea or acne vulgaris.
BRIEF DESCRIPTION OF THE DRAWINGS
[0175] FIG. 1 shows in vitro release profile of Example 1, 2, 3 and
ORACEA.RTM. in change over media (Acidic medium-pH1.2 and phosphate
buffer-pH 6.0).
[0176] FIG. 2 shows in vitro release profile of Example 3 and
ORACEA.RTM. in acetate buffer -pH 4.5.
[0177] FIG. 3 A. shows 12-hour Mean plasma doxycycline
concentration -Time profile of Example 3 administered to 52
subjects in fasting state.
[0178] FIG. 3 B. shows 72-hour Mean plasma doxycycline
concentration -Time profile of Example 3 administered to 52
subjects in fasting state.
DETAILED DESCRIPTION
Definitions
[0179] Unless otherwise defined, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art.
[0180] "Doxycycline" herein refers to any form of doxycycline
including hydrates such as doxycycline monohydrate, anhydrous
doxycycline, doxycycline base or acid addition salts of doxycycline
such as doxycycline hyclate or any other pharmaceutically
acceptable salt thereof in an amount of about 30 mg to less than 50
mg of doxycycline base or an equivalent amount of any other form of
doxycycline.
[0181] In the present application, the amount of doxycycline used
may be from about 30 mg to about 45 mg, or from about 35 mg to
about 45 mg, or from about 35 mg to about 40 mg, or from about 40
mg to about 45 mg of doxycycline base or an equivalent amount of
any other form of doxycycline. For example in the present
application, the doxycycline hyclate in an amount of about 46 mg
provides about 40 mg of doxycycline base similarly, where it is
stated that an amount of or range of one or more forms of
doxycycline is "based on the equivalent weight of doxycycline base"
or variances thereof, it is meant that the amount of that form or
forms of doxycycline will be sufficient to provide an equivalent
amount of doxycycline base. Thus, for example, about 35 mg to about
45 mg of doxycycline monohydrate based on the equivalent weight of
doxycycline base means enough doxycycline monohydrate so as to
provide 35 to 45 mg of doxycycline base. Unless stated otherwise,
these doses are the total daily dose. They can be given in a single
dosage form or multiple dosage forms, preferably in a single dosage
form given once a day.
[0182] The amount of doxycycline in certain embodiments thereof is
an amount sufficient to provide peak plasma concentration of
doxycycline from about 200 ng/ml to about 1000 ng/ml. The amount of
doxycycline per unit dosage form used in certain embodiments hereof
is an amount sufficient to provide an equivalent of about 30 mg to
about 40 mg of doxycycline base per dose per day or that provides
peak plasma concentration of doxycycline from about 200 ng/ml to
about 1000 ng/ml.
[0183] Doxycycline as used herein also encompasses their complexes,
polymorphs, hydrates, solvates, enantiomers or racemates. The solid
state of doxycycline used in the composition of the present
application is not critical. For example, doxycycline can be
amorphous or crystalline.
[0184] The term "about", as used herein, means within 10% of a
given value or range. Alternatively, the term "about" means within
an acceptable standard error of the mean as would be
appropriate.
[0185] The term "food effect", as used herein, refers to relative
difference in AUC (area under the curve AUC.sub.(0-t) and/or
AUC.sub.(0-.infin.),) or C.sub.max (maximum plasma concentration or
peak plasma concentration) of an active substance, when said
substance or a composition thereof, such as a tablet or a capsule,
is administered orally to a subject, concomitantly with food or in
a fed state as compared to the same values when the same substance
or a composition thereof is administered in a fasted state. [0186]
The food effect F is calculated as
[0186] F .times. .times. % = ( X fasted - X fed ) X fasted .times.
100 ##EQU00001## [0187] wherein X.sub.fed and X.sub.fasted are the
values of AUC (AUC.sub.(0-t) and/or AUC.sub.(0-.infin.)) or
C.sub.max in the fed and fasted state, respectively.
[0188] The term "reduced food effect", as used herein, refers to
the food effect in AUC (AUC.sub.(0-t) and/or AUC.sub.(0-.infin.))
and C.sub.max of a composition of doxycycline is less than about
15% and 40% respectively. In C.sub.max, "reduced food effect"
refers to food effect in C.sub.max of a composition of doxycycline
and is at least less than about 40%. In AUC, "reduced food effect"
refers to food effect in AUC (AUC.sub.(0-t) and/or
AUC.sub.(0-.infin.)) of a composition of doxycycline and is at
least less than about 15%. In another embodiment, the reduced food
effect is less than about 35% in terms of C.sub.max or less than
about 12% in terms of AUC. In still another embodiment both AUC and
C.sub.max are lower than the food effect of commerically available
40 mg doxycycline compositions as defined herein by at least about
15%.
[0189] Indeed, because of the reduced food effect of the present
invention particularly when compared to commercial products such as
ORACEA.RTM., it is possible to administer doxycycline to treat
inflammatory conditions or symptoms of inflammatory conditions (for
example, the papules and pustuals of acne vulgaris or rosacea) with
a reduced food effect. In some embodiments this may be accomplished
without need for normal administration warnings and/or without
requiring the patient be in a fasted state. Because of this, the
patient may take their doxycycline dose even less than an hour
before a meal, or two hours after a meal or otherwise in the fed
state.
[0190] The term "dC/dT" as used herein, refers to change in
doxycycline concentration in plasma as a function of time or change
in plasma concentration of doxycycline during the said time period
or interval. [0191] It is calculated as
[0191] dC .times. / .times. dT = ( Plasma .times. .times.
Concentration T .times. .times. 2 - Plasma .times. .times.
Concentration T .times. .times. 1 ) ( Time .times. .times. point 2
- Time .times. .times. point 1 ) ##EQU00002##
[0192] The term "modified release composition" herein refers to any
composition or dosage form which comprises an active drug and which
is formulated to provide a longer duration of pharmacological
response after administration of the dosage form than is ordinarily
experienced after administration of a corresponding immediate
release composition comprising the same drug in the same amount.
Modified release compositions include, inter alia, those
compositions described elsewhere as "controlled release", "extended
release", "delayed release", "sustained release", "prolonged
release", "programmed release", "time release" and/or "rate
controlled" compositions or dosage forms.
[0193] As used herein, the terms "composition" and "formulation"
are used interchangeably and refer to a mixture of two or more
compounds, elements, or molecules. Also the terms "composition" and
"formulation" may be used to refer to a mixture of one or more
active agents with a carrier or other excipients. Furthermore, the
term "dosage form" can include one or more composition(s) or
formulation(s) provided in a format for administration to a patient
in need thereof.
[0194] The term "Changeover dissolution study" herein refers to a
dissolution study performed by using USP apparatus I (Basket) with
50 rpm and the dissolution methodology includes two stages i.e.,
acid stage followed by buffer stage. Firstly in vitro dissolution
was carried out in acid stage pH 1.2 (750 ml of 0.1N HCl solution,
USP Type 1 apparatus at a speed of 50 rpm and 37.degree. C.) till
30 minutes and after 30 minutes the study was continued in buffer
stage (950 ml of phosphate buffer solution (pH 6.0), USP Type 1
apparatus at a speed of 50 rpm and 37.degree. C.). As used herein,
the term "commercially available 40 mg doxycycline composition"
refers to ORACEA.RTM. oral capsules containing doxycycline, USP in
an amount equivalent to 40 mg of anhydrous doxycycline, marketed by
Galderma Laboratories, L.P
FURTHER EMBODIMENTS
[0195] The present application relates to a modified release
composition doxycycline.
[0196] In another embodiment, the present application relates to a
modified release composition comprising: [0197] I. doxycycline;
[0198] II. one or more water soluble and insoluble polymers; and
[0199] III. one or more pharmaceutically acceptable excipients;
[0200] wherein said composition when subjected to a changeover
dissolution study releases no more than 20% in 30 minutes, in 750
ml of pH 1.2 acidic solution (0.1N HCl); and have at least one of
the following release profile in 950 ml of an pH 6.0 phosphate
buffer solution: [0201] a. less than about 30% in 35 minutes;
[0202] b. less than about 60% in 45 minutes; and [0203] c. more
than 85% in 60 minutes.
[0204] In another embodiment, the present application relates to a
modified release composition comprising: [0205] I. doxycycline;
[0206] II. one or more water soluble and insoluble polymers; and
[0207] III. one or more pharmaceutically acceptable excipients;
wherein said composition when subjected to a changeover dissolution
study releases no more than 10% in 30 minutes, in 750 ml of pH 1.2
acidic solution (0.1N HCl); and have at least one of the following
release profile in 950 ml of an pH 6.0 phosphate buffer solution:
[0208] a. less than about 30% in 35 minutes; [0209] b. less than
about 60% in 45 minutes; and [0210] c. more than 85% in 60
minutes.
[0211] In another embodiment, the present application relates to a
modified release composition comprising: [0212] I. about 46 mg of
doxycycline hyclate; [0213] II. one or more water soluble and
insoluble polymers; and [0214] III. one or more pharmaceutically
acceptable excipients; [0215] wherein said composition when
subjected to a changeover dissolution study releases no more than
30% in 30 minutes, in 750 ml of pH 1.2 acidic solution (0.1N HCl);
and have at least one of the following release profile in 950 ml of
an pH 6.0 phosphate buffer solution: [0216] a. less than about 30%
in 35 minutes; [0217] b. less than about 60% in 45 minutes; and
[0218] c. more than 85% in 60 minutes.
[0219] In another embodiment, the present application relates to a
modified release composition comprising: [0220] I. about 46 mg of
doxycycline hyclate; [0221] II. one or more water soluble and
insoluble polymers; and [0222] III. one or more pharmaceutically
acceptable excipients; [0223] wherein said composition when
subjected to a changeover dissolution study releases no more than
30% in 30 minutes, in 750 ml of pH 1.2 acidic solution (0.1N HCl);
and have at least one of the following release profile in 950 ml of
an pH 6.0 phosphate buffer solution: [0224] d. less than about 30%
in 35 minutes; [0225] e. less than about 60% in 45 minutes; [0226]
f. more than 85% in 60 minutes; [0227] and wherein said composition
upon oral administration to a human subjects in fasting state
provides at least one of the following pharmacokinetic parameters:
[0228] a. doxycycline plasma concentration of not more than about
15 ng/ml of doxycycline at 30 minutes; [0229] b. doxycycline plasma
concentration of not more than about 60 ng/ml of doxycycline at 45
minutes; [0230] c. doxycycline plasma concentration of not more
than about 200 ng/ml of doxycycline at 60 minutes; and [0231] d.
doxycycline plasma concentration from about 200 ng/ml to about 1000
ng/ml of doxycycline at above 90 minutes.
[0232] In another embodiment, the present application relates to a
modified release composition comprising: [0233] I. about 46 mg of
doxycycline hyclate; [0234] II. one or more water soluble and
insoluble polymers; and [0235] III. one or more pharmaceutically
acceptable excipients; [0236] wherein said composition when
subjected to a changeover dissolution study releases no more than
30% in 30 minutes, in 750 ml of pH 1.2 acidic solution (0.1N HCl);
and have at least one of the following release profile in 950 ml of
an pH 6.0 phosphate buffer solution: [0237] (a) less than about 30%
in 35 minutes; [0238] (b) less than about 60% in 45 minutes; and
[0239] (c) more than 85% in 60 minutes; [0240] and wherein said
composition upon oral administration in fasting state exhibits
bioequivalence to a commercially available 40 mg doxycycline
composition administered in fasting state and said bioequivalence
is established by: [0241] a. a 90% Confidence Interval for mean
AUC.sub.(0-t), which is between 80% and 125%, [0242] b. a 90%
Confidence Interval for mean AUC.sub.(0-inf), which is between 80%
and 125%, and [0243] c. a 90% Confidence Interval for mean
C.sub.max, which is between 80% and 125%.
[0244] In another embodiment, the present application relates to a
modified release composition comprising: [0245] I. about 46 mg of
doxycycline hyclate; [0246] II. one or more water soluble and
insoluble polymers; and [0247] III. one or more pharmaceutically
acceptable excipients; [0248] wherein said composition when
subjected to a changeover dissolution study releases no more than
30% in 30 minutes, in 750 ml of pH 1.2 acidic solution (0.1N HCl);
and have at least one of the following release profile in 950 ml of
an pH 6.0 phosphate buffer solution: [0249] a. less than about 30%
in 35 minutes; [0250] b. less than about 60% in 45 minutes; and
[0251] c. more than 85% in 60 minutes; [0252] and wherein said
composition upon oral administration in a fed state exhibits
bioequivalence to a commercially available 40 mg doxycycline
composition administered in fasting state and said bioequivalence
is established by: [0253] a. a 90% Confidence Interval for mean
AUC.sub.(0-t), which is between 80% and 125%; and [0254] b. a 90%
Confidence Interval for mean AUC.sub.(0-inf), which is between 80%
and 125%.
[0255] In another embodiment, the modified release composition of
doxycycline as per present application is used for the treatment of
rosacea in human subjects in need thereof.
[0256] In general the primary signs of rosacea are papules,
pustules, flushing, persistent redness, visible blood vessels,
bumps and pimples.
[0257] There are four subtypes of rosacea: [0258] Subtype 1
(erythematotelangiectatic rosacea), characterized by flushing and
persistent redness, and may also include visible blood vessels.
[0259] Subtype 2 (papulopustular rosacea), characterized by
persistent redness with transient bumps and pimples. [0260] Subtype
3 (phymatous rosacea), characterized by skin thickening, often
resulting in an enlargement of the nose from excess tissue, and
[0261] Subtype 4 (ocular rosacea), characterized by ocular
manifestations such as dry eye, tearing and burning, swollen
eyelids, recurrent styes and potential vision loss from corneal
damage.
[0262] In another embodiment, the modified composition of
doxycycline as per present application is used for treating
diseases or conditions in which collagenase is produced in
excessive amounts causing pathological destruction of tissues, such
as periodontal disease, rheumatoid arthritis, hyperparathyroidism,
diabetes and acne.
[0263] In another embodiment, the present application relates to a
method of treating rosacea in a human subject in need thereof
comprising: [0264] I. doxycycline, [0265] II. one or more water
soluble and insoluble polymers, and [0266] III. one or more
pharmaceutically acceptable excipients; [0267] wherein said
composition has reduced food effect, and said food effect is less
than about 35% in C.sub.max; and [0268] wherein said composition
upon oral administration in a fed state exhibits bioequivalence to
a commercially available 40 mg doxycycline composition administered
in fasting state and said bioequivalence is established by: [0269]
a. a 90% Confidence Interval for mean AUC.sub.(0-t), which is
between 80% and 125%; and [0270] b. a 90% Confidence Interval for
mean AUC.sub.(0-inf), which is between 80% and 125%.
[0271] In another embodiment, the present application relates to a
method of treating rosacea in a human subject in need thereof
comprising: [0272] I. about 46 mg of doxycycline hyclate, [0273]
II. one or more water soluble and insoluble polymers, and [0274]
III. one or more pharmaceutically acceptable excipients; [0275]
wherein said composition has reduced food effect, and said food
effect is less than about 35% in C.sub.max; and [0276] wherein said
composition upon oral administration in a fed state exhibits
bioequivalence to a commercially available 40 mg doxycycline
composition administered in fasting state and said bioequivalence
is established by: [0277] c. a 90% Confidence Interval for mean
AUC.sub.(0-t), which is between 80% and 125%; and [0278] d. a 90%
Confidence Interval for mean AUC.sub.(0-inf), which is between 80%
and 125%.
[0279] In another embodiment, the modified release composition
comprising doxycycline has reduced food effect and said food effect
is at least 15% lower compared to the food effect of commercially
available 40 mg doxycycline composition in C.sub.max and AUC
(AUC.sub.(0-t) and/or AUC.sub.(0-inf).
[0280] In another embodiment, the modified release composition
comprising doxycycline has reduced food effect and said food effect
is at least 20% lower compared to the food effect of commercially
available 40 mg doxycycline composition in C.sub.max and AUC
(AUC.sub.(0-t) and/or AUC.sub.(0-inf).
[0281] In another embodiment, the modified release composition
comprising doxycycline, has reduced food effect and said food
effect is at least 30% lower compared to the food effect of
commercially available 40 mg doxycycline composition in C.sub.max
and AUC (AUC.sub.(0-t) and/or AUC.sub.(0-inf).
[0282] In another embodiment, the modified release composition
comprising doxycycline has reduced food effect in AUC and said food
effect in AUC is at least 40% lower compared to the food effect in
AUC of commercially available 40 mg doxycycline composition in AUC
(AUC.sub.(0-t) and/or AUC.sub.(0-inf)).
[0283] In another embodiment, the modified release composition
comprising doxycycline has reduced food effect in AUC and said food
effect in AUC is at least 50% lower compared to the food effect in
AUC of commercially available 40 mg doxycycline composition in AUC
(AUC.sub.(0-t) and/or AUC.sub.(0-inf)).
[0284] In another embodiment, the present application relates to a
method of treating rosacea in a human subject in need thereof
comprising: [0285] I. doxycycline; [0286] II. one or more water
soluble and insoluble polymers; and [0287] III. one or more
pharmaceutically acceptable excipients; [0288] wherein said
composition has no food effect established by following parameters:
[0289] (a) a 90% Confidence Interval for mean AUC.sub.(0-t) of the
composition administered under fed state to human subjects is
within 80.00% to 125.00% of a AUC.sub.(0-t) of the composition
administered to human subjects in a fasting state; and [0290] (b) a
90% Confidence Interval for mean AUC.sub.(0-inf) of the composition
administered under fed state to human subjects is within 80.00% to
125.00% of a AUC.sub.(0-inf) of the composition administered to
human subjects in a fasting state.
[0291] In another embodiment, the present application relates to a
method of treating rosacea in a human subject in need thereof
comprising: [0292] I. about 46 mg of doxycycline hyclate, [0293]
II. one or more water soluble and insoluble polymers, and III. one
or more pharmaceutically acceptable excipients; [0294] wherein said
composition has no food effect established by following parameters:
[0295] (a) a 90% Confidence Interval for mean AUC.sub.(0-t) of the
composition administered under fed state to human subjects is
within 80.00% to 125.00% of a AUC.sub.(0-t) of the composition
administered to human subjects in a fasting state; and [0296] (b) a
90% Confidence Interval for mean AUC.sub.(0-inf) of the composition
administered under fed state to human subjects is within 80.00% to
125.00% of a AUC.sub.(0-inf) of the composition administered to
human subjects in a fasting state.
[0297] In another embodiment, the present application relates to a
method of treating rosacea in a human subject in need thereof
comprising: [0298] I. about 46 mg of doxycycline hyclate, [0299]
II. one or more water soluble and insoluble polymers, and [0300]
III. one or more pharmaceutically acceptable excipients; [0301]
wherein said composition has reduced food effect; and [0302]
wherein said composition upon oral administration in a fasting
state provides at least one of the following pharmacokinetic
parameters: [0303] a. doxycycline plasma concentration of not more
than about 15 ng/ml of doxycycline at 30 minutes; [0304] b.
doxycycline plasma concentration of not more than about 60 ng/ml of
doxycycline at 45 minutes; [0305] c. doxycycline plasma
concentration of not more than about 200 ng/ml of doxycycline at 60
minutes; and [0306] d. doxycycline plasma concentration from about
200 ng/ml to about 1000 ng/ml of doxycycline at above 90
minutes..
[0307] In another embodiment, the present application relates to a
method of treating or preventing rosacea in a patient known or
suspected to be in need of such treatment or prevention comprising
administering to the patient a modified release composition for
once daily oral administration in a human subject in need thereof
comprising [0308] I. about 46 mg of doxycycline hyclate; [0309] II.
one or more water soluble and insoluble polymers; and [0310] III.
one or more pharmaceutically acceptable excipients; [0311] wherein
said composition has dC/dT value less than about 80% of the dC/dT
value provided by the commercially available 40 mg doxycycline
composition, and said dC/dT is measured in a single dose human
pharmacokinetic study in fasting state and in a time period of
T.sub.0min to T.sub.60mins.
[0312] The AUC data from a food-effect study involving
administration of modified release composition comprising
doxycycline of present application under fasting state and fed
state (with a high-fat meal) provides exposure to the doxycycline
and wherein the exposure of doxycycline is not affected by food.
Therefore the modified release composition of present application
can be taken without regard to meals.
[0313] The AUC data from a food-effect study involving
administration of modified release composition comprising
doxycycline of present application under fasting state and fed
state (with meal) provides exposure to the doxycycline and wherein
the exposure of doxycycline is not affected by food. Therefore the
modified release composition of present application could be taken
without regard to meals.
[0314] In another embodiment, administration of the modified
release composition for once daily oral administration comprising
doxycycline to human subjects in need thereof of present
application may not require administration of adequate amounts of
fluid along with the said composition to wash down the composition
to reduce the risk of esophageal irritation and ulceration.
[0315] In another embodiment, the present application relates to a
modified release composition comprising [0316] I. about 46 mg of
doxycycline hyclate; [0317] II. one or more water soluble and
insoluble polymers; and [0318] III. one or more pharmaceutically
acceptable excipients; [0319] wherein said composition has dC/dT
value less than about 80% of the dC/dT value provided by the
commercially available 40 mg doxycycline composition, and said
dC/dT value is measured in a single dose human pharmacokinetic
study in a fasting state and in a time period of T.sub.0min to
T.sub.60mins.
[0320] In some aspects, the modified release composition comprising
about 46 mg of doxycycline hyclate has dC/dT value less than about
70% of the dC/dT value provided by the commercially available 40 mg
doxycycline composition, and said dC/dT value is measured in a
single dose human pharmacokinetic study in a fasting state and in
time period of T.sub.0min to T.sub.60mins.
[0321] In some aspects, the modified release composition comprising
about 46 mg of doxycycline hyclate has dC/dT value less than about
60% of the dC/dT value provided by the commercially available 40 mg
doxycycline composition, and said dC/dT value is measured in a
single dose human pharmacokinetic study in fasting state and in a
time period of T.sub.0min to T.sub.60mins.
[0322] In some aspects, the modified release composition for once
daily oral administration in a human subject in need thereof
comprising about 46 mg of doxycycline hyclate has dC/dT value less
than 50% of the dC/dT value provided by the commercially available
40 mg doxycycline composition, and said dC/dT value is measured in
a single dose human pharmacokinetic study in fasting state and in a
time period of T.sub.0min to T.sub.60mins.
[0323] In some aspects, the modified release composition comprising
about 46 mg of doxycycline hyclate has dC/dT value less than about
40% of the dC/dT value provided by the commercially available 40 mg
doxycycline composition, and said dC/dT value is measured in a
single dose human pharmacokinetic study in fasting state and in a
time period of T.sub.0min to T.sub.60mins.
[0324] In another embodiment, the modified release composition
comprising [0325] I. about 46 mg of doxycycline hyclate; [0326] II.
one or more water soluble and insoluble polymers; and [0327] III.
one or more pharmaceutically acceptable excipients; [0328] wherein
said composition has dC/dT value less than about 80% of the dC/dT
value provided by the commercially available 40 mg doxycycline
composition, and said dC/dT value is measured in a single dose
human pharmacokinetic study in a fasting state and in a time period
of T.sub.0min to T.sub.60mins; and wherein said composition has
reduced food effect.
[0329] In another embodiment, the modified release composition
comprising [0330] I. about 46 mg of doxycycline hyclate; [0331] II.
one or more water soluble and insoluble polymers; and [0332] III.
one or more pharmaceutically acceptable excipients; [0333] wherein
said composition has dC/dT value less than about 80% of the dC/dT
value provided by the commercially available 40 mg doxycycline
composition, and said dC/dT value is measured in a single dose
human pharmacokinetic study in a fasting state and in a time period
of T.sub.0min to T.sub.60mins; and wherein said composition has
reduced food effect, and said food effect is less than about 35% in
C.sub.max.
[0334] In another embodiment, the modified release composition
comprising [0335] I. about 46 mg of doxycycline hyclate; [0336] II.
one or more water soluble and insoluble polymers; and [0337] III.
one or more pharmaceutically acceptable excipients; [0338] wherein
said composition has dC/dT value less than about 80% of the dC/dT
value provided by the commercially available 40 mg doxycycline
composition, and said dC/dT value is measured in a single dose
human pharmacokinetic study in a fasting state and in a time period
of T.sub.0min to T.sub.60min; and wherein said composition has
reduced food effect, and said food effect is less than about 15% in
AUC.
[0339] In another embodiment, the modified release composition
comprising [0340] I. about 46 mg of doxycycline hyclate; [0341] II.
one or more water soluble and insoluble polymers; and [0342] III.
one or more pharmaceutically acceptable excipients; [0343] wherein
said composition has dC/dT value less than about 80% of the dC/dT
value provided by the commercially available 40 mg doxycycline
composition, and said dC/dT value is measured in a single dose
human pharmacokinetic study in a fasting state and in a time period
of T.sub.0min to T.sub.60min; and wherein said composition has
reduced food effect, and said food effect is less than about 12% in
AUC.sub.(0-t).
[0344] In another embodiment, the modified release composition
comprising [0345] I. about 46 mg of doxycycline hyclate; [0346] II.
one or more water soluble and insoluble polymers; and [0347] III.
one or more pharmaceutically acceptable excipients; [0348] wherein
said composition has dC/dT value less than about 80% of the dC/dT
value provided by the commercially available 40 mg doxycycline
composition, and said dC/dT value is measured in a single dose
human pharmacokinetic study in a fasting state and in a time period
of T.sub.0min to T.sub.60min; and wherein said composition has
reduced food effect, and said food effect is less than about 12% in
AUC.sub.(0-inf).
[0349] In another embodiment, the modified release composition
comprising doxycycline, wherein said composition has reduced food
effect and said food effect in C.sub.max is lower than the food
effect in C.sub.max of commercially available 40 mg doxycycline
composition by at least 15%.
[0350] In another embodiment, the modified release composition
comprising doxycycline, wherein said composition has reduced food
effect and said food effect in AUC is lower than the food effect in
AUC of commercially available 40 mg doxycycline composition by at
least 15%.
[0351] In another embodiment, the modified release composition
comprising doxycycline, wherein food effect of said composition is
at least 15% lower compared to the food effect of commercially
available 40 mg doxycycline composition.
[0352] In another embodiment, the present application relates to a
modified release composition comprising [0353] I. about 46 mg of
doxycycline hyclate; [0354] II. one or more water soluble and
insoluble polymers; and [0355] III. one or more pharmaceutically
acceptable excipients; [0356] wherein said composition has dC/dT
value less than 80% of the dC/dT value provided by the commercially
available 40 mg doxycycline composition, and said dC/dT value is
measured in a single dose human pharmacokinetic study in a fasting
state and in a time period of T.sub.0min to T.sub.60mins; [0357]
and wherein said composition provides C.sub.max from about 200
ng/ml to about 1000 ng/ml.
[0358] In another embodiment, the present application relates to a
modified release composition comprising [0359] I. about 46 mg of
doxycycline hyclate; [0360] II. one or more water soluble and
insoluble polymers; and [0361] III. one or more pharmaceutically
acceptable excipients; [0362] wherein said composition has dC/dT
value less than about 80% of the dC/dT value provided by the
commercially available 40 mg doxycycline composition, and said
dC/dT value is measured in a single dose human pharmacokinetic
study in fasting state and in a time period of T.sub.0min to
T.sub.60mins; and [0363] wherein said composition provides at least
one of the following pharmacokinetic parameters: [0364] a. average
input rate of from about 5 ng/hr/ml to about 8 ng/hr/ml during the
time period of T.sub.0min to T.sub.30mins. [0365] b. average input
rate of from about 15 ng/hr/ml to about 20 ng/hr/ml during the time
period of T.sub.0min to T.sub.60mins.
[0366] In another embodiment, the modified release composition
comprising (i) about 46 mg of doxycycline hyclate, (ii) one or more
water soluble and insoluble polymers and (iii) one or more
pharmaceutically acceptable excipients, wherein said composition
when administered to a human subject under fasting state provides
average input rate of about 5 ng/hr/ml to 8 ng/hr/ml during the
time period of T.sub.0mins to T.sub.30 mins.
[0367] In another embodiment, the modified release composition
comprising (i) about 46 mg of doxycycline hyclate, (ii) one or more
water soluble and insoluble polymers and (iii) one or more
pharmaceutically acceptable excipients, wherein said composition
when administered to a human subject under fasting state provides
average input rate of about 15 ng/hr/ml to 20 ng/hr/ml during the
time period of T.sub.0min to T.sub.60 mins.
[0368] In another embodiment, the modified release composition
comprising [0369] I. about 46 mg of doxycycline hyclate; [0370] II.
one or more water soluble and insoluble polymers; and [0371] III.
one or more pharmaceutically acceptable excipients; [0372] wherein
said composition has dC/dT value less than about 80% of the dC/dT
value provided by the commercially available 40 mg doxycycline
composition, and said dC/dT is measured in a single dose human
pharmacokinetic study in a fasting state and in a time period of
T.sub.0min to T.sub.60mins; and [0373] wherein said composition
upon oral administration in fasting state exhibits bioequivalence
to a commercially available 40 mg doxycycline composition
administered in fasting state and said bioequivalence is
established by: [0374] a. a 90% Confidence Interval for mean
AUC.sub.(0-t), which is between 80% and 125%, [0375] b. a 90%
Confidence Interval for mean AUC.sub.(0-inf), which is between 80%
and 125%, and [0376] c. a 90% Confidence Interval for mean
C.sub.max, which is between 80% and 125%.
[0377] In another embodiment, the modified release composition for
once daily oral administration in a human subject in need thereof
comprising [0378] I. about 46 mg of doxycycline hyclate; [0379] II.
one or more water soluble and insoluble polymers; and [0380] III.
one or more pharmaceutically acceptable excipients; [0381] wherein
said composition has dC/dT value less than about 80% of the dC/dT
value provided by the commercially available 40 mg doxycycline
composition, and said dC/dT is measured in a single dose human
pharmacokinetic study in a fasting state and in a time period of
T.sub.0min to T.sub.60mins; and [0382] wherein said composition
upon oral administration in a fed state exhibits bioequivalence to
a commercially available 40 mg doxycycline composition administered
in fasting state and said bioequivalence is established by: [0383]
a. a 90% Confidence Interval for mean AUC.sub.(0-t), which is
between 80% and 125%; and [0384] b. a 90% Confidence Interval for
mean AUC.sub.(0-inf), which is between 80% and 125%.
[0385] In another embodiment, the modified release composition of
the present application is orally administered once daily.
[0386] In another embodiment, the modified release composition of
the present application is orally administered twice daily.
[0387] In another embodiment, the modified release composition of
the present application is orally administered to human subjects in
need thereof.
[0388] In another embodiment, the modified release composition of
the present application comprises doxycycline, wherein said
doxycyline is an acid addition salt of doxycycline. In still
another aspect of this embodiment, the doxycycline is administered
in an amount of between about 30 and less than 50 mg, based on the
weight of doxycycline base, in yet another aspect, between about 35
and about 45 mg, and in yet a further aspect between about 35 and
about 40 mg of doxycycline base on the weight of doxycycline
base.
[0389] In another embodiment, the modified release composition of
the present application comprises doxycycline, which is doxycycline
hyclate.
[0390] In another embodiment, doxycycline hyclate is present in an
amount of about 46 mg.
[0391] In another embodiment, doxycycline hyclate is present in an
amount of 46.16 mg.
[0392] In another embodiment, the present application relates to a
modified release composition comprising (i) doxycycline hyclate,
(ii) one or more water soluble and insoluble polymers and (iii)
other pharmaceutically acceptable excipients.
[0393] In another embodiment, the present application relates to a
modified release composition of doxycycline for once daily
administration, wherein the said composition comprises of (i) one
or more core consisting of doxycycline, (ii) a release layer
containing one or more water soluble and insoluble polymers over
the core and (iii) one or more pharmaceutically acceptable
excipients.
[0394] In another embodiment, the present application relates to a
modified release composition of doxycycline for once daily
administration, wherein the said composition comprises of core
consisting of about 15-20% w/w of doxycycline, about 10-18% w/w one
or more water soluble and insoluble polymers and 1-20% of
pharmaceutically acceptable excipients, based on the total weight
of the final composition.
[0395] In another embodiment, the present application relates to a
modified release composition of doxycycline for once daily
administration, wherein the said composition comprises of core
consisting of about 15-20% w/w of doxycycline hyclate, about 10-18%
w/w one or more water soluble and insoluble polymers and 1-20% of
pharmaceutically acceptable excipients, based on the total weight
of the said composition.
[0396] In another embodiment, the present application relates to a
modified release composition of doxycycline for once daily oral
administration comprising one or more core comprising of about
15-20% w/w of doxycycline hyclate and the core is further coated by
release layer consisting of from about 10-18% w/w one or more water
soluble and insoluble polymers.
[0397] In one aspect the release layer release comprises a mixture
of at least one water soluble polymer and at least one water
insoluble polymer.
[0398] In another aspect, the release layer comprises of from about
5% w/w to about 40% w/w of water insoluble polymer and from about
2% w/w to 20% w/w of water soluble polymer, based on total weight
of the said composition.
[0399] In another aspect, the release layer comprises of from about
5% w/w to about 40% w/w of water insoluble polymer and from about
5% w/w to 15% w/w of water soluble polymer, based on total weight
of the said composition.
[0400] In another aspect, the release layer release comprises a
mixture of at least one water soluble polymer and at least one
water insoluble polymer and wherein the release layer has a
thickness of not more than 500 .mu.m.
[0401] In an aspect, the water insoluble polymer can be selected
from the group of pH-dependent polymer, hydrophobic polymer,
hydrophobic swellable polymer, hydrophobic non-swellable polymers
or mixtures thereof.
[0402] Examples of water insoluble polymer includes but not limited
to poly methacrylic acid derivatives, cellulose derivatives,
acrylic acid derivatives, maleic acid copolymers, polyvinyl
derivatives, Cellulose based pH dependent release retardant
polymers include hydroxypropylmethylcellulose acetate succinate,
hydroxypropylmethylcellulose phthalate, hydroxymethylethylcellulose
phthalate, cellulose acetate phthalate, cellulose acetate
succinate, cellulose acetate maleate, cellulose acetate trimelliate
cellulose benzoate phthalate, cellulose propionate phthalate,
methylcellulose phthalate, carboxymethylethylcellulose phthalate,
ethylhydroxyethylcellulose phthalate and the like, acrylic
copolymer based pH dependent release retardant include styrene,
acrylic acid copolymer, methyl acrylate, acrylic acid copolymer,
methyl acrylate, methacrylic acid copolymer, butyl acrylate,
methacrylic acid, methyl methacrylate copolymer (e.g. Trade-names:
Eudragit L 100 and Eudragit S, available from Rohm Pharma), ethyl
acrylate copolymer (e.g. Trade-name: Eudragit L 100-55, available
from Rohm Pharma), octyl acrylate copolymer, Maleic copolymer based
pH dependent release retardant include vinylacetate, maleic acid
anhydride copolymer, styrene, maleic acid anhydride copolymer,
styrene, maleic acid monoester copolymer, vinylmethylether, maleic
acid anhydride copolymer, ethylene, maleic acid anhydride
copolymer, vinylbutylether, maleic acid anhydride copolymer,
acrylonitrile, methyl acrylate, maleic acid anhydride copolymer,
butyl acrylate, styrene, maleic acid anhydride copolymer and the
like, Polyvinyl derivative based pH dependent release retardant
includes polyvinyl alcohol phthalate, polyvinylacetal phthalate,
polyvinyl butylate phthalate, polyvinylacetoacetal phthalate and
the like. Among these examples, methacrylic acid,
methylmethacrylate copolymer and methacrylic acid, ethylacrylate
copolymer are available under the brand name Eudragit.RTM..
[0403] In another aspect, the water soluble polymer can be selected
from the group of hydrophillic polymer, hydrophillic swellable
polymers, or hydrophillic non-swellable polymer or mixtures
thereof.
[0404] Examples of water soluble polymers include, but not limited
to, alkylcelluloses such as methylcellulose;
hydroxyalkylcelluloses, for example, hydroxymethyl cellulose,
hydroxypropylmethyl cellulose, hydroxyethyl cellulose,
hydroxypropyl cellulose and hydroxybutylcellulose;
carboxyalkylcelluloses such as carboxymethylcellulose; alKali metal
salts of carboxyalkylcelluloses such as sodium
carboxymethylcellulose; carboxyalkyl alkylcelluloses such,
carboxyalkylcellulose esters; other natural, semi-synthetic, or
synthetic polysaccharides such as alginic acid, alkali metal and
ammonium salts thereof, carrageenans, galactomannans, tragacanth,
agar-agar, gum arabic, guar gum, xanthan gum, starches, pectins,
such as sodium carboxymethyl amylopectin, chitin derivates such as
chitosan, polyfructans, inulin, sugars, lactose, sucrose, fructose,
mannitol, polyvinylalcohol, polyvinylpyrrolidone, polyalkylene
oxides such as polyethylene oxide and polypropylene oxide and
copolymers of ethylene oxide and propylene oxide, and other
materials known to one of ordinary skill in the art.
[0405] In another embodiment, the core comprises doxycycline and
additionally one or more pharmaceutically acceptable
excipients.
[0406] In some aspects, the inert core comprises at least one
pharmaceutically acceptable excipient selected from the group
consisting of: water soluble, water insoluble, water swellable or
water non swellable material. For example, the core may comprise
one or more of non-pareil seeds, pellets, beads, granules,
mini-tablets or a micro-tablet or a microcapsule, or a millisphere,
or a nanocapsule, or a nanosphere, or a microsphere. The non-pareil
seeds may be made up of any pharmaceutically acceptable excipients
such as starch, sugar, microcrystalline cellulose, inorganic salts
like crystal sodium chloride, vegetable gums, waxes, and the like.
The core may be readily available granulated products such as the
spherical granulation product of crystalline cellulose (trade name:
AVICEL.RTM. SP), the spherical granulation product of crystalline
cellulose and lactose (trade name: NONPAREIL.RTM. NP-5 and NP-7),
the spherical granulation product of refined sucrose (trade name:
NONPAREIL.RTM.-103), and the spherical granulation product of
lactose and alpha-converted starch. The core may also be prepared
with the techniques known to a person skilled in the art, such as
direct compression, wet granulation, dry granulation, or
extrusion-spheronization and the like.
[0407] In another embodiment, the active ingredient layer comprises
doxycycline, one or more hydrophilic polymer, or other
pharmaceutically acceptable excipients. In certain embodiment,
there may be one or more layers of active ingredients layer
comprising doxycycline. The core may consist of alternate layers of
active ingredient and release layer coat.
[0408] In another embodiment, the present application relates to a
modified release composition for once daily oral administration
that can be provided as granules or pellets filled in capsule or
sachets or the said composition can be compressed to form a
tablet.
[0409] In another embodiment, the oral once daily composition of
doxycycline as per present application can be provided as granules
or pellets which can be sprinkled on food.
[0410] In some aspects, in the pharmaceutical compositions
described herein having one or more excipients can perform more
than one function. All excipients can be used at levels well known
to the persons skilled in the art and within the acceptable
limits.
[0411] In another embodiment, the modified compositions of
doxycycline as described herein may comprise one or more
pharmaceutically acceptable excipients selected from diluent,
disintegrant, binder, lubricant, glidant, plasticizer, anti-tacking
agent, opacifying agent, and the like.
[0412] Suitable diluents may include one or more of
microcrystalline cellulose, starch, dibasic calcium phosphate,
tribasic calcium phosphate, calcium carbonate, dextrose, kaolin,
magnesium carbonate, magnesium oxide; sugars such as lactose or
sucrose; sugar alcohols such as mannitol, sorbitol or erythritol;
or mixtures thereof.
[0413] Suitable anti-tacking agents, lubricants or glidants may
include one or more of talc, metallic stearates such as magnesium
stearate, calcium stearate, zinc stearate; colloidal silicon
dioxide, finely divided silicon dioxide, stearic acid, hydrogenated
vegetable oil, glyceryl palmitostearate, glyceryl monostearate,
glyceryl behenate, polyethylene glycols, powdered cellulose,
starch, sodium stearyl fumarate, sodium benzoate, mineral oil,
magnesium trisilicate, Kaolin; or mixtures thereof. The
anti-tacking agent, lubricant or glidant may be used
interchangeably.
[0414] In one aspect, the compositions of the present application
comprising doxycycline, wherein said composition is dispensed in
HPMC capsules.
[0415] In another aspect, the compositions of the present
application comprising doxycycline, can be dispensed in capsules
containing not more than 2% w/w of gelatin.
[0416] In another embodiment, the present application relates to a
modified release composition for once daily oral administration to
a human in need thereof comprising doxycycline dispensed in HPMC
capsules that yields no more than 1% of hydrolytic impurity such as
4-epidoxycycline, when tested in 45.degree. C. and 75% relative
humidity for 24 hrs.
[0417] In another embodiment, the present application relates to a
process of preparing a modified release composition for once daily
oral administration to a human in need thereof comprising the steps
of: [0418] a) preparing doxycline solution comprising of
doxycycline, one or more hydrophilic polymer, or other
pharmaceutically acceptable excipients, [0419] b) layering the
doxycycline solution of step a) over the inert cores, [0420] c)
coating the cores of step b) with one or more water soluble and
insoluble polymers, [0421] d) lubricating the coated cores of step
c) and [0422] e) filling of cores of step d) in capsules or in
sachets or compressing into tablets.
[0423] All the layers, i.e. drug layer or the polymer layers, may
be applied as solution/dispersion of coating ingredients using any
conventional technique known in the art such as spray coating in a
conventional coating pan or fluidized bed processor or dip
coating.
[0424] The present application is further illustrated by the
examples which are provided merely to be exemplary of the
composition described above and do not limit the scope of the
application. Certain modifications and equivalents will be apparent
to those skilled in the art and are intended to be included within
the scope of the present application.
EXAMPLES
[0425] Examples 1 to Examples 3 illustrates the preparation of
doxycycline hyclate modified release dosage form, equivalent to 40
mg of doxycycline base.
Example 1
TABLE-US-00001 [0426] TABLE 1 Quantity per Unit (%) Ingredients
Examples 1 Examples 2 Examples 3 Drug Loading Doxycycline Hyclate
16.8 16.8 17.2 Hydroxypropylmethyl- 6.5 6.5 6.7 cellulose Sugar
Spheres 54.6 54.6 55.9 Polyethylene Glycol 400 1.9 1.9 2 Talc 1.9
1.9 2 Purified Water q.s q.s q.s Modified Release Coating
Methacrcylic acid 10.0 8.19 8.8 Copolymer (Type C) Hypromellose 3
Cps 5 4.0 4.4 (Methocel E3LV) Talc 3 0.3. 2.7. Acetone q.s. q.s.
q.s Water q.s. q.s. q.s. Lubrication Water q.s. 0.28 0.3 Total
Weight 100 100 100 Encapsulation Capsule shell size `1` (No.) 1 1
1
[0427] Procedure for manufacturing of doxycycline hyclate modified
release dosage form
[0428] A) Preparation of Drug Solution [0429] Doxycline solution
was prepared comprising of doxycycline, one or more hydrophilic
polymer, or other pharmaceutically acceptable excipients at a
temperature above 18.degree. C. and below 18.degree. C. [0430]
Note: It was found that doxycycline solution if prepared above
18.degree. C. leads to formation of hydrolytic impurity which does
not meet pharmacopoeial acceptable limits. [0431] Table 2 shows the
impurity levels of formulation prepared in different
conditions.
TABLE-US-00002 [0431] TABLE 2 Parameter 4-epidoxycycline (%) Cool
condition Time Room temperature (14.degree. C. .+-. 4.degree. C.)
Initial 0.08 0.03 24 hours 0.19 0.03
[0432] B) Drug Layering: [0433] Drug solution as prepared in step A
was layered onto sugar spheres.
[0434] C) Release Layer [0435] Mixture of methacrylic acid
copolymer and hypromellose were prepared in given solvents to form
a mixture, and to this talc was added and mixed well. This mixture
is sprayed onto drug coated pellets of Step B.
[0436] D) Lubrication & Filling [0437] The pellets of step C
were lubricated with talc in blender and filled in HPMC capsule
"size 1".
Example 4
[0438] The in vitro release study for the examples 1, 2 and 3 were
carried out in changeover media. It was performed by using USP
apparatus I (Basket) with 50 RPM and the dissolution methodology
includes change over mediums i.e., acid stage followed by buffer
stage. Table 3 shows dissolution profile of example 1, 2, 3 and
ORACEA.RTM.. [0439] First the in vitro dissolution was carried out
in acid stage (750 ml of 0.1N HCl solution, USP Type 1 apparatus at
a speed of 50 rpm and 37.degree. C.) till 30 minutes. After 30
minutes of in vitro dissolution of the same composition which is
used in acid stage was carried out in buffer stage (950 ml of
phosphate buffer solution (pH 6.0), USP Type 1 apparatus at a speed
of 50 rpm and 37.degree. C.). [0440] FIG. 1 shows the in vitro
release profile of composition of examples 1, 2 & 3 carried out
in change over media in comparison with ORACEA.RTM..
TABLE-US-00003 [0440] TABLE 3 Dissolution profile of examples 1, 2
& 3 (changeover media) Time point % Drug release (Minutes)
Example 1 Example 2 Example 3 ORACEA .RTM. Acid Stage 30 1 2 3 74
Acid + Buffer stage 30 1 2 3 74 35 3 7 6 74 45 41 56 48 76 60 93 93
98 93
Example 5
[0441] The in vitro release study for the example 3 was carried out
in 950 ml of 0.1N HCl media. It was performed by using USP
apparatus I (Basket) with 50 rpm. The dissolution data is given in
Table 4.
TABLE-US-00004 TABLE 4 Dissolution Data of example 5 (0.1N HCl
Media) Time point % Drug release 15 mins 1 30 mins 4 45 mins 20 60
mins 49
Example 6
[0442] The in vitro release study for the example 3 was carried out
in 950 ml of acetate buffer solution (pH 4.5), USP Type 1 apparatus
at a speed of 50 rpm and 37.degree. C. The dissolution data is
given in Table 5.
[0443] FIG. 2 shows the in vitro release profile of composition of
example 3 carried out in acetate buffer solution (pH 4.5) in
comparison with ORACEA.RTM..
TABLE-US-00005 TABLE 5 Dissolution Data of example 6 [acetate
buffer solution (pH 4.5)] % drug release Time point Example 1
Example 2 Example 3 ORACEA .RTM. 5 mins 0 1 1 19 15 mins 0 1 1 42
30 mins 2 3 4 58 45 mins 21 42 35 65 60 mins 72 89 78 68
Example 7
[0444] A single center, open-labeled, balanced, randomized,
3-treatment, 3-period, 6-sequence, single-dose, crossover,
comparative oral bioavailability study was conducted in 52 healthy
adult volunteers.
[0445] The treatments administered in the study were composition of
example 3 under the fasting condition (Treatment A), composition of
example 3 under the fed condition (Treatment B) and ORACEA under
the fasting condition (Treatment C). [ORACEA.RTM. (Doxycycline,
USP) Capsules 40 mg, capsules of Galderma Laboratories, L.P., USA,
Batch No. 1300342A, Expiry date: January 2016]
[0446] The subjects were fasted overnight for at least 10 hours
before receiving a single dose of either composition of example 3
or ORACEA for Treatment A and C.
[0447] In Treatment B, the subjects were fasted overnight for at
least 10 hours before receiving an FDA-standardized high-fat,
high-calorie breakfast (800-1000 kcal) (FDA Guidance 2002),
followed by administration of a single dose of composition of
example 3.
[0448] A washout period of 7 days was maintained between the dosing
of investigational products in consecutive study periods. Blood
samples were collected to determine the plasma concentrations of
doxycycline before dosing (pre-dose) and at 0.5, 0.75, 1, 1.33,
1.67, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 12, 16, 24, 48 and
72 hours after dosing.
[0449] The concentrations of doxycycline in plasma were determined
by using a validated LC/MS-MS method.
[0450] The pharmacokinetic (PK) parameters C.sub.max, AUC.sub.0-t,
AUC.sub.0-inf, % Residual area, T.sub.lag, T.sub.max, t.sub.1/2 and
K.sub.el were calculated using a non-compartmental analysis (NCA)
model.
[0451] The primary PK parameters, C.sub.max, AUC.sub.0-t,
AUC.sub.0-inf were tested statistically for the effects of period,
treatment, sequence and subject nested within sequence using the
mixed-effect analysis of variance (ANOVA) method.
[0452] The geometric least squares means of C.sub.max, AUC.sub.0-t,
AUC.sub.0-inf derived from the ANOVA were compared for
bioequivalence under the fasting state and the food-effect and
presented in terms of 90% confidence intervals of the test product
(composition of example 3) to the comparator product (ORACEA)
ratios.
[0453] The comparisons of interest were Treatment A vs. C for the
bioequivalence assessment under fasting condition and Treatment B
vs A for the food-effect and Treatment B vs. C.
[0454] At the end of the study following parameters are evaluated:
[0455] a. Plasma concentration profile of Doxycyline v. time [0456]
b. Bioequivalence study v. ORACEA.RTM. capsules [0457] c. Food
effect study and [0458] d. dC/dT evaluation
[0459] a. Plasma Concentration Profile of Doxycyline v. Time
[0460] The plasma concentration of Doxycyline from Example 3 v.
time was plotted for 12 hrs and 72 hrs respectively. FIG. 3 A.
shows 12-hour mean plasma doxycycline concentration-time profile
and FIG. 3 B. shows 72-hour mean plasma doxycycline
concentration-time profile of example 3 administered to 52 subjects
in fasting state.
[0461] The plasma concentration of example 3 vis-a-vis ORACEA.RTM.
for initial time point upto 60 minutes is shown Table 6.
TABLE-US-00006 TABLE 6 Time points Plasma concentration (ng/ml/hr)
(mins) Example 3 ORACEA .RTM. 0 0 0 30 6.57 219 45 49.75 344 60
117.03 378
[0462] b. Bioequivalence Study v. ORACEA.RTM. Capsules
[0463] It was observed that the example 3 and ORACEA.RTM. 40 mg
capsules met the bioequivalence criteria as of 90% confidence
intervals of Cmax and AUC parameters were within the acceptance
range of 80.00% to 125.00%, in fasting conditions.
TABLE-US-00007 TABLE 7 Bioequivalence study Treatment A Treatment B
Treatment C PK Example 3 Example 3 ORACEA .RTM. Parameters
(Fasting) (Fed) 40 mg- Fasting C.sub.max 473.65 .+-. 178.79 325.32
.+-. 75.66 466.40 .+-. 156.90 AUC.sub.0-t 6109.48 .+-. 1703.82
5443.45 .+-. 1209.17 6239.96 .+-. 1538.03 AUC.sub.0-inf 6448.19
.+-. 1768.20 5780.34 .+-. 1269.96 6561.49 .+-. 1602.90 Tlag.sup.a
(hr) 0.495 (0.00-0.999) 2.00 (0.501-3.50) 0.00 (0.00-0.00)
Tmax.sup.a (hr) 2.99 (0.745-4.00) 5.49 (2.49-7.00) 1.99
(0.744-4.11) T.sub.1/2 el (hr) 16.48 .+-. 3.40 16.50 .+-. 3.26
16.28 .+-. 3.87 .sup.aMedian (Min-Max)
[0464] c. Food Effect Study
[0465] The composition of example 3 was evaluated for its food
effect vis-a-vis ORACEA.RTM.. The composition of example 3
exhibited a food effect of about 31% in C.sub.max and further
showed reduction of about 31% in food effect when compared to food
effect of ORACEA.RTM.. The results are shown in Table 8.
TABLE-US-00008 TABLE 8 Food effect The following table lists the
food effect values of composition of Example 3 and ORACEA .RTM.
Food Effect Reduction of Food ORACEA .RTM. Effect of Example 3 PK
Example 3 Example 3 Disclosed compared to Food Parameters (Fasting)
(Fed) Example 3 in label Effect of ORACEA .RTM. (%) Cmax 473.65
325.23 31.31% 45% 30.42% AUC.sub.0-t 6109.48 5443.45 10.90% 22%
50.45% AUC.sub.0-inf 6448.19 5780.34 10.35% 21% 50.71%
[0466] d. dC/dT Evaluation
[0467] The rate of change of doxycycline plasma concentration
during the time period of T.sub.0mins-T.sub.60mins was tabulated in
Table 9. The rate of change of doxycycline plasma concentration
during the time period of T.sub.0min-T.sub.60mins of example 3 was
less than 80% of rate of change of doxycycline plasma concentration
during the time period of T.sub.0min-T.sub.60mins of ORACEA.RTM..
The rate of change of doxycycline plasma concentration during 0-1
hrs of example was 117.03 ng/ml/hr and ORACEA.RTM. was 378
ng/ml/hr.
[0468] Calculation of dC/dT for example 3:
[0469] Plasma Concentration.sub.T2: 117.303 ng/ml
[0470] Plasma Concentration.sub.T1: 0 ng/ml
[0471] Time point.sub.2: 1 hr [0472] Time point.sub.1: 0 hr
[0472] dC .times. / .times. dT = ( Plasma .times. .times.
Concentration T .times. .times. 2 - Plasma .times. .times.
Concentration T .times. .times. 1 ) ( Time .times. .times. point 2
- Time .times. .times. point 1 ) ##EQU00003## dC .times. / .times.
dT = ( 11 .times. 7 . 0 .times. 3 - 0 ) ( 1 - 0 ) ##EQU00003.2## dC
.times. / .times. d .times. T = .times. 1 .times. 1 .times. 7 . 3
.times. 03 .times. .times. ng .times. / .times. ml .times. .times.
/ .times. hr ##EQU00003.3##
[0473] Calculation of dC/dT for ORACEA.RTM.:
[0474] Plasma Concentration.sub.T2: 378 ng/ml
[0475] Plasma Concentration.sub.T1: 0 ng/ml
[0476] Time point.sub.2: 1 hr [0477] Time point.sub.1: 0 hr
[0477] dC .times. / .times. dT = ( Plasma .times. .times.
Concentration T .times. .times. 2 - Plasma .times. .times.
Concentration T .times. .times. 1 ) ( Time .times. .times. point 2
- Time .times. .times. point 1 ) ##EQU00004## dC .times. / .times.
dT = ( 378 - 0 ) ( 1 - 0 ) ##EQU00004.2## dC .times. / .times. d
.times. T = .times. 378 .times. .times. ng .times. / .times. ml
.times. .times. / .times. hr ##EQU00004.3##
TABLE-US-00009 TABLE 9 dC/dT values: Change in Doxycline
concentration as a function of time Time (Hrs.) Example 3 ORACEA
.RTM. 0.0 to 1 117.03 ng/ml/hr 378 ng/ml/hr
[0478] Although the invention herein has been described with
reference to particular embodiments, it is to be understood that
these embodiments are merely illustrative of the principles and
applications of the present invention. It is therefore to be
understood that numerous modifications may be made to the
illustrative embodiments and that other arrangements may be devised
without departing from the spirit and scope of the present
invention as defined by the appended claims.
* * * * *