U.S. patent application number 10/978246 was filed with the patent office on 2005-05-26 for dosage form with a core tablet of active ingredient sheathed in a compressed annular body of powder or granular material, and process and tooling for producing it.
Invention is credited to Aqua, Ofer, Fleshner-Barak, Moshe, Lerner, E. Itzhak, Rosenberger, Vered.
Application Number | 20050112202 10/978246 |
Document ID | / |
Family ID | 26993007 |
Filed Date | 2005-05-26 |
United States Patent
Application |
20050112202 |
Kind Code |
A1 |
Lerner, E. Itzhak ; et
al. |
May 26, 2005 |
Dosage form with a core tablet of active ingredient sheathed in a
compressed annular body of powder or granular material, and process
and tooling for producing it
Abstract
A solid dosage form for oral administration to a patient
comprising a core tablet sheathed in an annular body of compressed
powder or granular material is provided. A preferred embodiment of
the solid dosage form reduces contact of the active ingredient in
solid form with the mucosa lining the gastrointestinal tract, which
is particularly advantageous for delivering an ulcerative drug. A
tool set comprising a columnar punch and a punch assembly
comprising an annular punch and core rod, and a tableting process
for making the solid dosage form are also provided.
Inventors: |
Lerner, E. Itzhak; (Petach
Tikva, IL) ; Rosenberger, Vered; (Jerusalem, IL)
; Aqua, Ofer; (Ofra, IL) ; Fleshner-Barak,
Moshe; (Petach Tikva, IL) |
Correspondence
Address: |
KENYON & KENYON
ONE BROADWAY
NEW YORK
NY
10004
US
|
Family ID: |
26993007 |
Appl. No.: |
10/978246 |
Filed: |
October 29, 2004 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10978246 |
Oct 29, 2004 |
|
|
|
10419536 |
Apr 21, 2003 |
|
|
|
10419536 |
Apr 21, 2003 |
|
|
|
10291619 |
Nov 12, 2002 |
|
|
|
60342442 |
Dec 24, 2001 |
|
|
|
60361821 |
Mar 4, 2002 |
|
|
|
Current U.S.
Class: |
424/470 |
Current CPC
Class: |
A61K 9/2095 20130101;
A61K 9/209 20130101; A61J 3/005 20130101; A61K 31/663 20130101;
A61P 19/10 20180101; A61K 31/216 20130101; A61K 31/4045 20130101;
A61K 9/2072 20130101; A61K 31/433 20130101; A61K 45/06 20130101;
A61K 31/195 20130101; B30B 11/34 20130101; A61J 3/10 20130101 |
Class at
Publication: |
424/470 |
International
Class: |
A61K 009/26 |
Claims
1-19. (canceled)
20. A toolset for producing a solid pharmaceutical dosage form
comprising a core tablet sheathed in a compressed annular body of
powder or granular material, the toolset comprising: a) a columnar
punch, and b) a punch assembly comprising an annular punch and a
core rod slidably engageable with the annulus of the annular punch,
wherein the core rod is capable of movement between a retracted
position and an extended position and wherein the core rod is
biased in an extended position.
21. The toolset for producing a solid pharmaceutical dosage form of
claim 20 further comprising a die with a bore therethrough wherein
the extent of movement between the retracted and extended positions
is approximately equal to or less than the thickness of the
die.
22. The toolset of claim 20 wherein the columnar punch has a
contact face with a centered protrusion.
23. The toolset of claim 20 adapted for use in a press having a die
table for mounting a die with a bore therethrough such that the
axis of the bore is normal to the die table, a first actuated
reciprocating ram movable along the axis of the bore and a second
actuated reciprocating ram on the opposite side of the die table
from the first actuated reciprocating ram movable along the axis of
the die bore independently of the first ram, wherein: a) the
columnar punch is adapted for mounting to one of the reciprocating
rams of the press, and has an end sized to be received in the die
bore, b) the annular punch is adapted for mounting to the other of
the reciprocating rams of the press and has an end sized to be
received in the die bore, and c) the punch assembly further
comprises a collar adapted for mounting to a fixed point on the
press coaxially with the die bore and wherein the core rod is
slidably engaged within the annulus of the collar and biased by
biasing means housed in the collar.
24. The toolset of claim 20 adapted for use in a press having: a
generally planar and circular die table capable of rotation about
an axis normal to the plane and having a plurality of bores
therethrough around its circumference at regular intervals, a first
punch carrier mounted on one side of the die table and a second
punch carrier mounted on the other side of the die table, each
punch carrier rotating about the axis synchronously with the die
table and provided with a plurality of vertical holes or slots for
receiving punches, each hole or slot being in registry with a bore
through the die table, means for controlling the motion of punches
in the direction of the axis, wherein: a) the columnar punch is
adapted for slidable engagement with the holes or slots in the
first punch carrier and has an end sized to be received in a bore,
b) the annular punch is adapted for slidable engagement with the
holes or slots in the second punch carrier and has an end sized to
be received in a bore, and c) the core rod is capable of
independent motion relative to the annular punch.
25. A process for producing a solid pharmaceutical dosage form
comprising forming an annular body of powder or granular material
around a core tablet by compression.
26. The process for producing a solid pharmaceutical dosage form of
claim 25 wherein forming the annular body comprises: a) filling an
annular cavity with the powder or granular material, the annular
cavity being defined by: i) the bore of a die, ii) an annular punch
partially inserted into the bore from one side, iii) a core rod in
an extended position wherein it extends through the bore and the
annular punch with its tip substantially flush with the surface of
the die on the side opposite the annular punch, wherein the core
rod is movable between the extended position and a retracted
position wherein the tip is inside the bore, and further wherein
the core rod is biased in the extended position, b) placing the
core tablet at the tip of the core rod, and c) advancing a columnar
punch toward the bore from the side of the die opposite the annular
punch, thereby pushing the core tablet into the bore against the
bias force on the core rod and causing the core rod to retract, and
compressing the powder or granular material around the core tablet,
forming the annular body.
27. The process of claim 26 wherein the columnar punch contact face
has a centered protrusion.
28. The process for producing a solid pharmaceutical dosage form of
claim 26 further comprising withdrawing at least one of the punches
from the die bore after advancing the columnar punch toward the
bore and ejecting the solid pharmaceutical dosage form from the
bore.
29. The process for producing a solid pharmaceutical dosage form of
claim 25, which uses a tablet press equipped with the following
parts and tooling: a die table mounting a die with a bore extending
therethrough, a columnar punch mounted on one side of the die table
coaxially with the bore and movable along the axis of the bore with
the end proximal to the die table sized to be received into the
bore and being terminated with a contact face for pressing against
the powder or granular material, an annular punch mounted on the
other side of the die table coaxially with the bore and movable
along the axis of the die bore independently of the columnar punch,
wherein the end of the annular punch proximal to the die table is
sized to be received into the die bore and is terminated with a
contact face for pressing against the powder or granular material,
and a core rod slidably engaged within the annulus of the annular
punch and aligned coaxially with the die bore, the core rod
moveable between a retracted position and an extended position
wherein the core rod extends through the die bore with the tip of
the rod substantially flush with the surface of the die, the core
rod being biased to the extended position by biasing means, wherein
forming the annular body comprises: a) filling an annular cavity
with the powder or granular material, the annular cavity being
defined by the die bore, the core rod in its extended position and
the contact face of the annular punch partially inserted into the
bore, b) placing the core tablet at the tip of the extended core
rod, c) advancing the columnar punch, whereby the core tablet is
pushed into the die bore against the bias force exerted by the core
rod biasing means, whereby the core rod at least partially
retracts, and whereby the powder or granular material is compressed
between the contact faces of the columnar and annular punches,
forming the annular body.
30. The process for producing a solid pharmaceutical dosage form of
claim 29 further comprising withdrawing at least one of the punches
from the die bore after advancing the columnar punch toward the
bore and ejecting the solid pharmaceutical dosage form from the
bore.
31. The process of claim 29 wherein the columnar punch contact face
has a centered protrusion.
32. The process for producing a solid pharmaceutical dosage form of
claim 29 wherein the die table is horizontal, the columnar punch is
above the die table, and the annular punch is below the die table,
wherein the tablet press is further equipped with a feed shoe for
delivering the powder or granular material to the die bore from
above and a collar fixedly mounted below the die table coaxially
with the die bore, the core rod being slidably engaged within the
annulus of the collar and biased by bias means housed in the
collar, and wherein, the annular cavity is filled from the feed
shoe, the columnar punch is withdrawn after the advancing step and
the solid pharmaceutical dosage form is ejected from the bore by
advancing the annular punch into the bore.
33. The process of claim 32 wherein the annular cavity is filled by
placing the feed shoe over the die bore while the annular punch is
positioned with its contact face approximately flush with the die
surface and then lowering the lower punch to form the cavity and
drawing the powder or granular material into the cavity by gravity
or pressure differential.
34. The process for producing a solid pharmaceutical dosage form of
claim 25 which uses a tablet press equipped with the following
parts and tooling: a generally planar and circular die table
capable of rotation about an axis normal to the plane and having a
plurality of bores therethrough around its circumference at regular
intervals, a first punch carrier mounted on one side the die table
and a second punch carrier mounted on the other side of the die
table, each punch carrier rotating about the axis synchronously
with the die table and provided with a plurality of vertical holes
or slots, each hole or slot being in registry with a bore through
the die table, a plurality of annular first punches, each slidably
engaged within one of the vertical holes or slots of the first
punch carrier, each of the first punches having an end proximal to
the die table sized to be received into a bore and being terminated
with an annular contact face for pressing against the powder or
granular material, each of the first punches further having a core
rod slidably engaged within the annulus and aligned coaxially with
a die bore, the core rod moveable between a retracted position and
an extended position wherein the core rod extends through the die
bore with the tip of the rod substantially flush with the surface
of the die table, the core rod being biased to the extended
position by biasing means, a plurality of second punches, each
slidably engaged within one of the vertical holes or slots of the
second punch carrier, each of the second punches having an end
proximal to the die table sized to be received into a bore and
terminated with a contact face for pressing against the powder or
granular material, means for controlling the motion of the punches
in the direction of the axis, wherein forming the annular body
comprises: a) filling an annular cavity with the powder or granular
material, the annular cavity being defined by a die bore, a core
rod in its extended position and the contact face of a first punch
partially inserted into the bore, b) placing the core tablet at the
tip of the extended core rod, c) advancing a second punch into the
die bore, whereby the core tablet is pushed into the die bore
against the bias force exerted by the core rod biasing means,
whereby the core rod at least partially retracts, and whereby the
powder or granular material is compressed between the contact faces
of the first and second punch, forming the annular body.
35. The process for producing a solid pharmaceutical dosage form of
claim 34 further comprising withdrawing at least one of the punches
from the die bore after advancing the second punch toward the bore
and ejecting the solid pharmaceutical dosage form from the
bore.
36. The process of claim 34 wherein the second punch contact face
has a centered protrusion.
37. The process of claim 34 wherein the annular cavity is filled by
rotating the die table under a feed shoe while the first punch is
positioned with its contact face substantially flush with the die
table surface and then retracting the first punch to form the
cavity and drawing the powder or granular material into the cavity
by gravity or pressure differential.
38. A solid pharmaceutical dosage form produced by the process of
claim 25.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 10/291,619, filed Nov. 12, 2002, which claims
the benefit of provisional application Ser. No. 60/342,442, filed
Dec. 24, 2001, and provisional application Ser. No. 60/361,821,
filed Mar. 4, 2002, all of which are incorporated herein by
reference.
FIELD OF THE INVENTION
[0002] The present invention relates to powder molding,
pharmaceutical dosage forms, tableting processes and equipment, and
improved solid dosage forms for oral delivery of drugs that cause
contact irritation or ulceration to the lining of the esophagus and
stomach.
BACKGROUND OF THE INVENTION
[0003] Gastrointestinal side effects are a common and serious
problem with many drugs. These side effects may manifest themselves
in nausea or diarrhea or with injury to the gastrointestinal
mucosa. Many drugs have been shown to cause damage to the mucosal
lining of the esophagus (esophagitis) or the stomach (gastritis).
Among the drugs known to cause such damage are non-steroidal
anti-inflammatory drugs ("NSAIDs"). See A. A. al-Quorain et. al.,
"Non Steroidal Anti-inflammatory Drug Induced Gastropathy", J. Int.
Med. Res. 1993, 21(2), 89-97; P. M. Goggins et. al., "Prevalence of
Heliobacter Pylori Infection and its Effect on Symptoms and
non-Steroidal Anti-inflammatory Drug Induced Gastro-intestinal
Damage in Patients with Rheumatoid Arthritis" Gut, 1993, 34(12),
1677-80; M. Frezza et. al., "The Histopathology of Non-Steroidal
Anti-inflammatory Drug Induced Gastroduodenal Damage: Correlation
with Heliobacter Pylori, Ulcers and Haemorrhagic Events" J. Clin.
Pathol. 2001, 54(7), 521-5 and references therein. Other drugs
known to cause such damage are bisphosphonates. See K. O. Larsen,
"Oesophagusskader Relatert till Bisphosphonater" Tidsskr. Nor.
Laegeforen 2000, 120(20), 2397-9; D. Y. Graham, H. M. Malaty,
"Alendronate and Naproxen Are Synergic for Development of Gastric
Ulcers" Arch. Inter. Med. 2001 , 161(1), 107-110; F. L. Lanza et.
al., "Endoscopic Comparison of Esophageal and Gastroduodenal
Effects of Risedronate and Alendronate in Postmenopausal Women"
Gastroenterology, 2000, 119(3), 631-8.
[0004] In the case of NSAIDs, bisphosphonates and many other drugs,
there is much evidence to implicate the solid form of the drug in
causing esophagitis and gastritis. See D. Jasperson, "Drug Induced
Esophageal Disorders:pathnogenesis, Incidence, Prevention and
Management" Drug Saf 2000, 22(3), 237-249; S. J. Smith et al.,
"Pill-induced Esophagitis Caused by Oral Rifampin" Ann.
Pharmocother. 1999, 33(1), 27-31; J. W. Kikendall, "Pill
Esophagitis" J. Clin. Gastroenterol. 1999, 28(4), 298-305; A.
Minchoa, D. S. Greenbaum, "Pill Esophagitis Caused by Non-steroidal
Antiinflammatoy Drugs" Am. J. Gasterenterol., 1991, 86(8), 1086-9.
Such esophagitis is called pill induced esophagitis or pill
esophagitis and when causing damage to the stomach lining can be
called contact gastritis. These forms of mucosal damage can be
mitigated by preventing the physical contact of the drug containing
solid dose formulation with the surface of the mucosa.
[0005] Pill esophagitis and contact gastritis can be reduced by
limiting physical contact between the pill containing the drug and
the mucosal lining. Solutions suggested in the literature include
coatings to limit esophageal contact, coatings to shorten
esophageal transit time and improvements in tablet shape to shorten
esophageal transit time. See A. C. Perkins et. al., "The Use of
Scintigraphy to Demonstrate the Rapid Esophageal Transit of the
Oval Film-coated Placebo Risendronate Tablet Compared to a Round
Uncoated Placebo Tablet When Administered with Minimal Volumes of
Water" Int. J. Pharm., 2001, 222(2) 295-303; T. S-H. Chen, U.S.
patent application Ser. No. 2001/0036475; A. G. Daifotis et. al.,
U.S. Pat. No. 5,994,329 (enteric coatings and film coatings through
which the drug is released). Each of these methods has a drawback.
Coatings that come off in the stomach may be removed earlier than
planned while in the esophagus leading to esophagitis. Furthermore,
such coatings will not prevent gastritis. Coatings or shape
improvements that shorten esophageal transit time can help prevent
esophagitis but again not gastritis. Enteric coatings can totally
envelope the pill until it is in the small intestine. While this
can prevent contact esophagitis or gastritis it will not protect
against ulceration in the small intestine and will not be desired
for a drug whose absorption site is in the upper part of the GI
tract (stomach or duodenum).
[0006] A further suggestion to prevent contact between the solid
particles of the drug formulation and the mucosal lining is to
encapsulate the drug totally in a capsule or coating and release
the drug slowly through an orifice or through the film coat by
diffusion or through micropores. These suggestions can be fulfilled
by using an osmotic pump device to deliver the drug or a permeable
film coat such as Eudragit NE or Eudragit RL or RS. The osmotic
pump idea is not a promising solution to the problem of contact
esophagitis and gastritis. While the drug leaves the osmotic pump
in solution in most cases, the osmotic agents themselves are
ulcerative in high concentrations. The stream of drug plus osmotic
agent leaving the orifice causes ulceration, especially if the
device has lodged against the mucous membrane See V. Simko et. al.,
"Increased Risk in Esophageal Obstruction with Slow Release
Medications" J. Assoc. Acad. Minor. Phys., 1997, 8(2), 38-42. A
permeable film coat can serve as a solution to the problem but it
limits the drug release profile attainable since only relatively
slower release profiles will be obtained and immediate release, or
very short slow release profiles are not compatible with the film
coat.
[0007] In view of the foregoing, it would be highly desirable to
have a versatile solid dosage form that reduces contact between the
lining of the gastrointestinal tract and a drug contained in the
dosage form, particularly an ulcerative drug. Accordingly, one
object of the present invention is to provide a solid dosage form
that can release a drug according to a predetermined release
profile and reduce contact of the solid drug with the lining of the
gastrointestinal tract during transit of the dosage form through
the esophagus, stomach and intestine.
[0008] A novel set of tooling and tableting process have been
invented to produce a dosage form meeting the foregoing stringent
requirements on tableting presses that are presently available from
commercial sources. Tableting presses are well known and available
in many designs, and with an array of features. Some presses with
high throughput capacity are designed for large production runs.
Others are adapted for application of compression coatings,
production of multilayer tablets or engraving. Design features
which are desirable in presses to be used with the novel toolset of
this invention will become apparent from consideration of the
detailed description of the preferred embodiments of the invention
which follows.
[0009] U.S. Pat. No. 5,071,607 describes a pair of dies (punches)
with piercing means biased into a sheathed position, which, when
used to compress a coating about an object, pierce the object. The
punches are adapted for piercing an osmotic drug dispensing
vehicle. The piercing means are integral to the punches. They are
moved from a sheathed to an unsheathed position by compressive
force from punch actuators. Being integral with the punches, the
piercing means are not capable of motion or stasis independent of
the motion of the punches.
[0010] U.S. Pat. No. 3,146,169 describes a tablet comprising a
medicated portion and a non-medicated inert portion of sublimed
sulfur, plastic, bone phosphate, barium sulfate, wax, calcium
silicate and or aluminum silicate which covers part but not all of
the surface of the medicated portion. The function of the inert
portion is to expose to the gastric fluids only a portion of the
surface of the medicated portion (through a single hole in the
inert portion) so as to slow the rate of release relative to a
conventional tablet and maintain the rate of release constant. The
tablet is made by feeding the space between the upper and lower
punch faces of a compression coating machine successive batches of
material; first, granules of inert material; second, a preformed
core of the medicated material; and third, more granules of the
inert material. The upper punch face is provided with a protrusion
so that when the punch faces are brought together the inert
material is compressed around the inner medicated core in the form
of a layer provided with a hole made by the protrusion on the upper
punch face. The protrusion is pointed and forms a single hole in
the medicated portion as well as the inert portion.
[0011] U.S. Pat. No. 5,551,856 describes an apparatus for
connecting an assembly of three concentrically aligned movable
punches which are independently actuated by hydraulic means to a
main body of a pressing machine.
[0012] In view of the foregoing, there is a need for a versatile
solid dosage form that reduces contact between the mucosa lining
the gastrointestinal tract and a solid drug contained in the dosage
form and equipment and a process for producing such a dosage
form.
SUMMARY OF THE INVENTION
[0013] One object of the invention is to provide a novel solid
dosage form for oral administration to a patient wherein the active
ingredient is contained in a core tablet that is sheathed in a
compressed annular body of powder or granular material formed
around the core tablet by compression.
[0014] Another object of the invention is to provide a solid dosage
form for oral administration to a patient that reduces contact
between the mucosa lining the gastrointestinal tract and a solid
drug contained in the dosage form. In satisfaction of this object
there is provided a preferred embodiment of the solid dosage form
in which the core tablet is recessed in the annular body to shield
it from contact with the mucosa lining the gastrointestinal tract.
The solid dosage form is well suited for oral delivery of
ulcerative active ingredients like bisphosphonates and NSAIDs. In
an especially preferred dosage form embodiment, the annular body
has opposed annular faces that are aligned substantially coaxially
with recessed opposing surfaces of the core tablet. The opposed
surfaces of the core tablet are substantially exposed to the
external environment and drug release occurs from the exposed
surfaces.
[0015] In a second dosage form embodiment, which is suitable for
use with non-ulcerative drugs, the opposed surfaces of the core
tablet are not recessed. Rather, they are flush with the annular
faces of the annular body.
[0016] Another object of the invention is to provide a toolset that
can be used with commercially available tableting presses to make
the solid dosage forms of the invention. The toolset comprises a
generally columnar punch having a contact face for pressing against
a powder or granular material. The contact face has a protrusion
near its center if the upper punch is to be used to make a
compacted dosage form with a recessed core tablet. The toolset
further comprises a punch assembly comprising an annular punch and
a core rod slidably engageable with the annulus of the annular
punch and capable of movement between a retracted position and an
extended position, the core rod being biased in an extended
position when the toolset is in use.
[0017] Yet another object of the invention is to provide a process
for making the solid dosage forms of the invention. In its
particulars, the process comprises filling an annular cavity
defined by a die bore, the core rod and the contact face of the
annular punch with a powder or granular material, positioning a
core tablet atop the tip of the core rod and advancing the columnar
punch into the die bore.
[0018] The columnar punch pushes the core tablet into the die bore
against the bias force exerted by the core rod. If the columnar
punch is equipped with a protrusion, the protrusion pushes the core
tablet into the die. Otherwise, the contact surface of the columnar
punch pushes the core tablet into the die bore. As the core tablet
is pushed into the die bore, the core rod retracts against the bias
force. Meanwhile, the action of the columnar punch compresses the
powder or granular material into an annular body around the core
tablet.
[0019] The process further comprises withdrawing at least one of
the punches from the bore and ejecting the finished dosage form,
such as withdrawing the columnar punch and advancing the annular
punch to eject the dosage form.
BRIEF DESCRIPTION OF THE FIGURES
[0020] FIG. 1 shows sectional perspective, side and top down views
of a solid dosage form with a recessed core tablet of active
ingredient in a compressed annular body of powder or granular
material in accordance with the invention.
[0021] FIG. 2 is a perspective view of a single station tableting
press shown with the toolset installed.
[0022] FIG. 3 is a sectional side view of the columnar punch and
punch assembly.
[0023] FIGS. 4a-4e are sectional side views depicting stages in a
cycle of operation from delivery of powder or granular material to
ejection of a finished tablet at a tableting station equipped with
a toolset in accordance with the invention.
[0024] FIG. 5 is a plot of the average rate of alendronate
excretion in urine of humans who had taken a dosage form in
accordance with the present invention containing 70 mg monosodium
alendronate and a prior art 70 mg monosodium alendronate dosage
form.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0025] The present invention provides a novel solid dosage form, as
well as tooling and a process for producing the novel dosage form.
Preferred embodiments of the invention are well suited for the
administration of ulcerative drugs. As used in this disclosure, the
term "ulcerative" in reference to an active pharmaceutical
ingredient, drug or excipient means that when the drug or excipient
is contacted as a solid with the mucosa lining at least a portion
of the gastrointestinal tract it causes erosive damage.
Alendronate, other bisphosphonates and NSAIDS that non-selectively
inhibit the COX-1 and COX-2 enzyme are ulcerative drugs.
[0026] The novel dosage form comprises a core tablet containing an
active pharmaceutical ingredient sheathed in an annular body
comprised of compressed powder or granular material. The core
tablet has first and second opposed surfaces and a circumferential
surface. "Sheathing" means that the annular body encircles the core
tablet and is in contact with the core tablet about its
circumferential surface, but leaves opposed surfaces of the core
tablet substantially exposed. The core tablet contains at least one
active pharmaceutical ingredient, but otherwise its formulation is
not critical to the invention. The core tablet can be formulated
for any desired release profile, such as immediate release, delayed
release, burst or pulsed release, sustained or zero order release.
The annular body can be formulated to achieve any desired purpose,
such as gastric retention, ease of swallowing, taste masking and
control of the rate of drug release from the core tablet. The
annular body also can contain or be coated with a co-active
ingredient.
[0027] The type of drug to be delivered also is not an essential
element of the invention. The terms "drug" and "active
pharmaceutical ingredient" broadly include any biologically,
physiologically, or pharmacologically active the agent. Active
pharmaceutical ingredients that can be administered in the
compressed dosage form of the present invention include adrenergic
receptor agonists and antagonists; muscarinic receptor agonists and
antagonists; anticholinesterase agents; neuromuscular blocking
agents; ganglionic blocking and stimulating agents; sympathomimetic
drugs; serotonin receptor agonists and antagonists; central nervous
system active drugs such as psychotropic drugs, antipsychotic
drugs, antianxiety drugs, antidepressents, antimanic drugs,
anesthetics, hypnotics, sedatives, hallucinogenic drugs and
antihallucinogenic drugs; antiepileptic drugs; antimigraine drugs;
drugs for treatment of Parkinson's, Alzheimer's and Huntington's
disease; analgesics; antitussive agents; antihistaminic drugs;
H.sub.1, H.sub.2, and H.sub.3 receptor antagonists; bradykinin
receptor antagonists; antipyretic agents; antiinflammatory agents;
NSAIDs; diuretics; inhibitors of Na.sup.+--Cl.sup.- symport;
vasopressin receptor agonists and antagonists; ACE inhibitors;
angiotensin II receptor antagonists; renin inhibitors; calcium
channel blockers; .beta.-adrenergic receptor antagonists;
antiplatelet agents; antithrombic agents; antihypertensive agents;
vasodialators; phosphodiesterase inhibitors; antiarrhythmic drugs;
HMG CoA reductase inhibitors; H.sup.+, K.sup.+-ATPase inhibitors;
prostaglandins and prostaglandin analogs; laxatives; antidiarrheal
agents; antiemetic agents; prokinetic agents; antiparasitic agents
such as antimalarial agents, antibacterial agents, drugs for
treatment of protozoal infections and antihelmintic drugs;
antimicrobial drugs such as sulfonamides, quinolones, .beta.-lactam
antibiotics, aminoglycosides, tetracyclines, chloramphenicol and
erythromycin; drugs for treatment of tuberculosis, drugs for
treatment of leprosy; antifungal agents; antiviral agents;
antineoplastic agents; immunomodulators; hematopoietic agents;
growth factors; vitamins; minerals; anticoagulants; hormones and
hormone antagonists such as antithyroid drugs, estrogens,
progestins, androgens, adrenocortical steroids and adrenocortical
steroid inhibitors; insulin; hypglycemic agents; calcium resorption
inhibitors; clucocorticoids; retinoids and heavy-metal
antagonists.
[0028] The annular body can be formed of any powdered or granular
pharmaceutically acceptable excipients and can itself include a
pharmaceutically active ingredient. In particular, it may be
mentioned that diluents, binders, disintegrants, glidants,
lubricants, flavorants, colorants and the like can be included in
the annular body. Powdering and granulation with conventional
excipients and the techniques for forming compressed bodies
therefrom with given characteristics in terms of friability,
hardness and freedom from capping is well within the knowledge of
those skilled in the art of tableting.
[0029] Preferred excipients for forming the annular body include
hydroxypropyl cellulose (e.g., Klucel.TM.), hydroxypropyl
methylcellulose (e.g. Methocel.TM.), microcrystalline cellulose
(e.g., Avicel.TM.), starch, lactose, sugars, polyvinylpyrrolidone
(e.g., Kollidon.TM., Plasdone.TM.) and calcium phosphate.
[0030] In an especially preferred compressed dosage form
illustrated in FIG. 1, core tablet 1 containing the active
pharmaceutical ingredient is recessed in the annular body 2, which
is composed of non-ulcerative pharmaceutical excipients. The
"recessed" tablet is especially well suited for oral delivery of
ulcerative drugs. It reduces the incidence of pill esophagitis and
contact gastritis by localizing the ulcerative drug in a core
tablet that is shielded from contact with the mucosa lining the
gastrointestinal tract. The drug is shielded because the core
tablet is recessed. Recessing the core tablet does not
significantly alter the release profile of the core tablet because
a sizable portion of the surface of the core tablet is in fluid
communication with the environment. In contrast, in coated or
encapsulated dosage forms, the coating or capsule must be breached
by gastric fluid before the drug is released. In the present
invention, the outer contour of the dosage form protects the mucosa
lining the gastrointestinal tract without interrupting fluid
communication between the core tablet and the environment.
[0031] Exemplary of drugs that can be advantageously delivered
using the preferred recessed dosage form of this invention are
monosodium alendronate monohydrate, monosodium alendronate
trihydrate, sodium etidronate, sodium risedronate, pamidronate,
aspirin, ibuprofen, naproxen, fenoprofen, ketoprofen, oxaprozin,
flubiprofen, indomethacin, sulindac, etodolac, mefenamic acid,
meclofenamate sodium, tolmetin, ketorolac, diclofenac, piroxicam,
meloxicam, tenoxicam, phenylbutazone and oxyphenbutazone.
[0032] Turning again to FIG. 1, core tablet 1 has opposed first and
second surfaces 3 and 4 and an outer circumferential surface 5
extending between the opposed surfaces. Core tablet 1 is preferably
cylindrical or disk shaped for ease of manufacture, but need not be
so. In a dosage form for administration to humans, the maximum
distance across either of the opposed surfaces 3 or 4 is preferably
from about 2 mm to about 12 mm, more preferably from about 4 mm to
about 7 mm, most preferably about 5 mm. Opposed surfaces 3 and 4
can be flat, concave or convex and are preferably flat for bearing
modest axial compression forces exerted by flat pressing surfaces
during formation of the annular body about the core tablet.
[0033] In outer contour, annular body 2 is preferably cylindrically
shaped, but it can have any cross section, such as oval, elliptical
or oblong. The outer diameter is preferably of from about 5 mm to
about 15 mm, more preferably of from about 7 mm to about 12 mm,
most preferably about 9 mm. The inner diameter can be any size up
to about 2 mm less than the outer diameter. A narrow inner diameter
less than 2 mm may slow release of the drug if an excipient in the
annular body swells upon contact with gastric fluid. However, in
some embodiments, a lower limit 0.5 mm may still be useful.
Preferably, the inner diameter is 3 mm or greater.
[0034] Annular body 2 has opposed first and second annular faces 6
and 7, an outer circumferential surface 8 extending between the
annular faces from their outer edges, and an inner circumferential
surface 9 extending between the annular surfaces from their inner
edges, thus defining an annulus.
[0035] As best seen in side view (FIG. 1B), inner circumferential
surface 9 of annular body 2 consists of three longitudinal (axial)
segments. First and second segments 10 and 11 are terminal and do
not contact the sides of the core tablet. They are separated by an
internal third segment 12 that contacts the outer circumferential
surface 5 of core tablet 1. Opposed surfaces 3 and 4 of the core
tablet are therefore recessed from annular faces 6 and 7 of the
annular body. Opposed surfaces 3 and 4 are preferably recessed from
about 0.5 mm to about 4 mm, more preferably about 1.5 mm relative
to the annular faces 6 and 7 of the annular body (said recessed
distance corresponding to the length of the corresponding terminal
segment). The recess depth of surfaces 3 and 4 can be the same or
it can be different.
[0036] By recessing the drug-containing core tablet, any contact
between the dosage form and the gastrointestinal mucosa occurs with
a surface of the annular body formed of non-ulcerative excipients,
and optionally one or more non-ulcerative co-active ingredient,
rather than with the solid ulcerative active ingredient. However,
one or both of opposed surfaces 3 and 4 can be flush with annular
faces 6 and 7 of the annular body without deleterious effect when
the dosage form of the present invention is used to administer
non-ulcerative drugs.
[0037] To better apprehend the preferred recessed dosage form
embodiment of the invention, it is useful to conceive of surface 3
of the core tablet and first longitudinal segment 10 as defining a
first void 13. Likewise, surface 4 of the core tablet and second
longitudinal segment 11 define a second void 14. Voids 13 and 14
fill with gastric fluid when the dosage form is immersed in gastric
fluid after reaching the stomach. Gastric fluid passes through the
voids to contact the core tablet and the drug leaves through the
voids after it is dissolved. Voids 13 and 14 are preferably from
about 0.5 mm to about 10 mm, more preferably from about 3 mm to
about 6 mm and most preferably about 4.5 mm in width (measured
parallel to first or second opposed surfaces). Drug release,
therefore, does not occur by an osmotic mechanism such as occurs
with pierced dosage forms made using the apparatus of U.S. Pat. No.
5,071,607. Rather, in a large still fluid environment, drug
concentration drops off roughly isotropically and exponentially by
diffusion. In contrast, osmotic release of the drug product would
produce a streaming flow that can cause locally high concentrations
of the drug and osmotic agents at considerable distance from the
tablet. Osmotic streams highly concentrated in an ulcerative drug
are potentially irritating to the mucosa, just like the solid drug,
particularly if the tablet is lodged in a fold in the
gastrointestinal wall.
[0038] Opposed surfaces 3 and 4 of the core tablet are preferably
substantially exposed, i.e. are not substantially covered by the
annular body. "Substantially exposed" means that less than about
50% of each of the opposed surfaces is concealed or hidden from
visual inspection by the annular body. A portion of opposed
surfaces 3 and 4 can be concealed by the annular body because of
differences between the diameter and shape of the core tablet and
the diameter and shape of certain pressing portions of the tooling
used to compress the annular body, as will become apparent from
consideration of the description of the tooling aspect of the
invention. Such differences may result in inner segment 12 being
offset from terminal segments 10 and 11, which, themselves, can
have different longitudinal cross sections, e.g. have different
diameters, as depicted in FIG. 1. Alternatively, the cross section
of the annulus defined by inner circumferential surface 9 can be
uniform throughout its length. Although a portion of opposed
surfaces 3 and 4 can be concealed by the annular body that is not
necessarily the case.
[0039] The solid dosage forms with a drug-containing core tablet
sheathed in a compressed annular body of non-ulcerative excipients
can be produced using a novel toolset that constitutes a second
aspect of the invention.
[0040] The toolset can be used in conjunction with conventional
tablet presses such as rotary presses and reciprocating presses or
with presses that have been specially designed and manufactured.
Examples of commercially available rotary presses are the Manesty
Express 25, the Kilian RUD or RTS series and comparable equipment.
Examples of commercially available reciprocating presses are the
Manesty F3 and comparable equipment made by Stokes, Kilian and Key
Industries.
[0041] The principle elements of the toolset are a columnar punch
and a punch assembly comprising an annular punch having an annulus
(or bore), a core rod slidably engageable within the annulus of the
annular punch, wherein the core rod is capable of movement between
a retracted position and an extended position, the core rod being
biased in the extended position. The columnar punch and punch
assembly are sized and shaped to fit into the die bore of a rotary
or reciprocating tablet machine.
[0042] The toolset is well adapted for use with conventional single
station tablet presses in which opposing upper and lower punches
cooperatively compress a powder or granular material within a die.
Referring to FIG. 2, single station presses are provided with a
horizontal die table 15 having an aperture for receiving a die 16
and associated gripping means for locking the die into position.
Dies for such presses customarily have opposed flat surfaces with a
centrally located bore 17 having a highly polished wall surface
extending from surface to surface and a circumferential locking
groove 18 for engaging the gripping means. The bore serves as a
receptacle for receiving powder or granular material to be
compressed when the lower punch is partially inserted. The rims of
the bore are customarily chamfered to help guide the punches into
the bore. The bore's cross section determines the size and shape of
the finished tablet in cross section. The quantity of material and
pressure of compression determine the tablet's height. The bore can
be cylindrical, but also can be any other shape.
[0043] In operation, the bore is filled with material and the upper
punch is inserted into the bore and pressed against the material
under high pressure thereby compressing the powder or granulated
material into a tablet between the pressing, or contact, surfaces
of the punches.
[0044] Together, the wall of the bore and the contact surfaces of
the upper and lower punches define a mold that determines the size
and surface contours of the final product. The final product can
have any external contour by selection of appropriate bore shape
and contact face contour.
[0045] After compression, the upper punch is withdrawn and the
lower punch is advanced to eject the tablet.
[0046] The upper and lower punches are advanced and withdrawn by
independently actuated upper and lower reciprocating rams 19 and
20. Customarily, single punch presses are also provided with a
stationary mounting point 21 below the die table coaxial with the
aperture.
[0047] A toolset of this invention adapted for use in a single
station press comprises a columnar punch and a punch assembly
comprising a collar, core rod and annular punch.
[0048] Referring now to FIG. 3, columnar punch 22 can be of a
conventional columnar shape and is provided with locking means,
such as locking flat 23 to secure it to the upper reciprocating ram
19 of the tablet press.
[0049] Columnar punch 22 includes a contact face 24. Contact face
24 can have any desired contour, e.g. standard concave, deep
concave, extra deep concave, modified ball or flat. Preferably, the
contour of contact face 24 is flat with a beveled edge.
[0050] A columnar punch for use in producing a dosage form of the
present invention having a recessed core also has a protrusion 25
centrally located on the contact face 24, as illustrated.
Preferably, the height of protrusion 25 is from about 0.5 mm to
about 4 mm, more preferably about 1.5 mm. The shape of the
protrusion is preferably cylindrical or tapered cylindrical but can
also be oval, ellipsoid, oblong or any other shape desired. The
protrusion is preferably cylindrical and has a flat raised surface
26. Protrusion 25 preferably has a diameter of from about 3 mm to
about 7 mm, more preferably about 4.5 mm. In other embodiments,
particularly suited to use when non-ulcerative active
pharmaceutical ingredients are to be administered, protrusion 25 is
absent.
[0051] Punch assembly 27 comprises collar 28, core rod 29 slidably
engaged with collar 28 and annular punch 30 slidably engageable
with core rod 29.
[0052] Collar 28 is provided with mounting means, such as external
threads 31 around its circumference for mounting to stationary
mounting point 21 located below the die table.
[0053] As illustrated, the distal end 32 of collar 28 relative to
the die table when installed, has a gripping section (shown with
optional hexagonal cross section) for gripping by a wrench for
mounting to stationary mounting point 21. At the proximal end 33 of
the collar 28 relative to the die table when installed, the annulus
is dimensioned to receive and guide the core rod 29.
[0054] Away from the proximal end of the collar, the diameter of
the annulus is substantially greater than that of the core rod to
provide a housing 34 for a biasing means such as spring 35. The
coils of spring 35 encircle the core rod. Although a coil spring 35
is a preferred biasing means, biasing can be accomplished by other
means, such as a stack of Belleville washers or an elastic
insert.
[0055] Spring 35 or other biasing means engages retaining ring 36
mated to core rod 29. Retaining ring 36 can be mated to the core
rod by clamping engagement with a circumferential groove 37 in the
rod. The retaining ring can be a conventional C-clip which engages
the groove, or it can be a clamp or any other structure against
which the biasing means can exert a biasing force and which is
restrained from movement relative to core rod 29 in a direction
parallel to the long axis of the core rod.
[0056] As illustrated, an annular locking bolt 38 engages internal
threads 39 at the distal end of collar 32. The bore 40 through
locking bolt 38 is dimensioned to receive and, in conjunction with
the annulus at the proximal portion of the collar, to restrain
motion of core rod 29 to axial movement. Locking bolt 38 also
retains and can compress the biasing means. Core rod 29 is biased
in the direction of the die table when the collar is installed on
stationary mounting point 21 and is retained in slidable engagement
with collar 28 by retaining ring 36 and locking bolt 38. The height
of rod tip 41 is adjusted by advancing or retracting collar 28
relative to stationary mounting point 21, e.g. by rotating the
collar when in threaded engagement with the stationary mounting
point.
[0057] Core rod 29 can vary in diameter along its length. A
preferred diameter of rod tip 41 is from about 0.5 mm to about 10
mm, more preferably about 4.5 mm. However, for rigidity, the core
rod should be thicker, preferably from about 4 mm to about 12 mm
throughout most of its length, more preferably about 9 mm. The rod
can taper gradually from a narrow diameter at the tip to a larger
shank diameter or it can change abruptly at a shoulder 42.
[0058] The core rod can be of two-piece construction. For instance,
the core rod tip 41 could be adapted to attach to the core rod by
providing external threads at its lower end and a socket with
internal threads at the upper end of the core rod, or vice versa. A
two-piece construction allows the core rod tip to be replaced if it
is damaged or if a core rod tip of a different shape is desired.
The core rod tip can have any desired diameter or shape.
[0059] Punch assembly 27 further comprises annular punch 30.
Annular punch 30 is provided with means for attaching to lower
reciprocating ram 20, such as locking flat 43. The bore 44 through
annular punch 30 is dimensioned to receive and surround core rod 29
while permitting axial movement of annular punch 30 independent of
the core rod. The bore through annular punch 30 can vary in
diameter along the length of the punch providing an annular flange
45 for engagement with shoulder 42 on the core rod. Engagement of
flange 45 with shoulder 42 prevents annular punch 30 and collar 28
from abutting each other during handling and installation. Annular
punch contact surface 46 presses against the powder or granular
material during compression. Contact face 46 can have any desired
contour, e.g. standard concave, deep concave, extra deep concave,
modified ball or flat. Preferably contact face 46 is flat with a
beveled edge for ease of ejection of the finished tablet.
[0060] The columnar punch, annular punch, core rod and collar are
preferably made of metal, more preferably steel, most preferably
stainless steel.
[0061] In the final dosage form with recessed core tablet, the
depth of first void 13 (FIG. 1) is determined by the height of
protrusion 25. The depth of second void 14 is determined by the
fill depth, strength of the bias on the core rod, the
compressibility of the material and the thickness of the core
tablet. These parameters can be adjusted by routine experimentation
to control the depth of second void 14, which is suitably
commensurate with the depth of first void 13.
[0062] In a second dosage form embodiment, either one or both of
opposed surfaces 3 and 4 of the core tablet are flush with the
annular faces 6 and 7 of the annular body 2. This alternative
embodiment can be produced by using a columnar punch as previously
described but lacking a protrusion 25. Surface 3 will generally be
flush with annular face 6 if the columnar punch has a flat contact
face. Whether the opposed surface 4 is flush with annular face 7
will depend on the fill depth, compressibility of the powder or
granular material and thickness of the core tablet, which factors
can be adjusted by routine experimentation to yield a dosage form
with surface 4 recessed the desired distance relative to annular
face 7.
[0063] To further illustrate the invention and the operation of the
toolset, a cycle of operation will now be described. The cycle of
operation is embodied in a process that constitutes a third aspect
of the invention.
[0064] The cycle of operation is first illustrated on a single
station press. The cycle begins with the first action that occurs
after ejection of the tablet formed in a previous cycle. Referring
now to FIG. 4a, feed shoe 47 moves laterally over the die bore
while the annular punch 30 is in an advanced position such that
contact surface 46 is substantially flush with the top surface of
the die. In so doing, the feed shoe sweeps a finished tablet from
atop the annular punch toward a chute leading to a receptacle where
the tablets are collected. Annular punch 30 is retracted while the
tip 41 of core rod 29 remains flush with the die surface (FIG. 4b).
Retraction of the annular punch causes an annular cavity to form
into which particles of the powder or granular material are fed
from the feed shoe by gravity and/or pressure differential. Once
the cavity is filled, the feed shoe is shifted away from the die
bore.
[0065] Pre-compressed core tablet 1 is positioned atop the core rod
using any conventional apparatus for producing tablets with a
compressed coating such as that of a Kilian RUD press (FIG. 4c).
The positioning means forms no part of the invention and has been
omitted for clarity.
[0066] Columnar punch 22 is advanced by upper reciprocating ram 19
(FIG. 4d). As columnar punch 22 approaches the bore, the raised
surface 26 of protrusion 25 presses upon core tablet 1. As columnar
punch 22 enters bore 17, core tablet 1 is pushed into the bore by
the protrusion against the biasing force exerted on core rod 29.
Continued movement of columnar punch 22 into the die bore
compresses the powder or granular material into an annular body
around the core tablet. Strong compressive forces can be exerted on
the powder or granular material without breaking the core tablet
because the core tablet travels into the bore before the powder or
granular material is fully compressed.
[0067] Those skilled in the art may also appreciate that protrusion
25 could be replaced with a core rod in the columnar punch that is
biased toward an extended position so that the tip of the rod would
press against core tablet 1 during compression. Such a core rod for
the columnar punch would not necessarily be attached to a
stationary mounting point on the press. It would be biased with
greater force than core rod 29 so that pressure exerted by the
columnar punch would push the core tablet into the bore against the
resistence of the core rod.
[0068] After the powder or granular material is compressed, the
columnar punch is withdrawn. Either concurrently or subsequently,
annular punch 30 is advanced by lower reciprocating ram 20 to a
position such that contact face 46 is substantially flush with the
upper surface of the die to elevate the finished tablet above the
die where it can be swept from the die table in a subsequent cycle
of operation (FIG. 4e). Meanwhile, the core rod is biased back to
its original position flush with the die surface.
[0069] The toolset is well adapted for use in a rotary tablet
press. The cross-sectional dimension and shape of the columnar
punch, and the dimensions and shape of the protrusion (if present)
are the same as in a punch adapted for use in a reciprocating
tablet press. The other dimensions of the toolset are generally
dictated by the dimensions and layout of a particular tableting
press. These dimensions can be readily determined by those skilled
in the art. The cross-sectional dimensions and shape of the annular
punch and of the core rod are the same as in a punch adapted for
use in a reciprocating tablet press, again with other dimensions
being dictated by the dimensions and layout of a particular
tableting press. These dimensions can be readily determined by
those skilled in the art. In addition, the punches include
conventional bearing surfaces at the end distal to their contact
surfaces for engaging the cams and rollers that control their
motion along the axis of the die bore, such as those shown in the
patents that are incorporated by reference below.
[0070] In an annular punch for use in a rotary machine, the core
rod biasing means preferably is housed in the annular punch and
includes a means for adjusting the degree of extension of the core
rod and/or the bias, such as a set screw or similar device.
[0071] Conventional rotary tablet presses are well known in the
art. Some rotary presses and improvements related thereto are
described in U.S. Pat. Nos. 5,462,427, 5,234,646, 5,256,046 and
5,635,223, which are incorporated herein by reference in their
entirety. Rotary presses have a moving die table that rotates
around a vertical axis. Mounted above and below the die table are
upper and lower punch carriers that rotate synchronously with the
die table. The punch carriers can be generally drum shaped bodies
of about the same diameter as the die table or they can have arms
that extend outward from a lesser diameter ring. The punch carriers
are provided with a plurality of vertical holes or slots at regular
intervals around their circumference or through the ends of the
arms. When the press is in operation, punches are inserted into
each slot with their contact faces pointing toward the die table.
Each punch has a bearing means at the end opposite the contact
face. The bearing means engage stationary cams and rollers which
control the vertical motion of each punch during a cycle of
operation. The cams and rollers are arranged such that in a cycle
of operation, a powder or granular material is fed into a die while
the lower punch is inserted into the die. Pressure is applied to
the powder or granular material to produce a compressed body. After
compression, one or more of the punches is removed from the die and
the dosage form is released. Rotary presses are especially suited
for high volume production because they typically contain numerous
punch and die sets operating simultaneously.
[0072] A cycle of operation using the toolset of this invention
adapted for use in a rotary press will now be described. As the die
table rotates, one of the dies passes under a fill shoe or force
feeder. While the die is passing underneath the shoe or feeder, the
annular punch is withdrawn by the cam. The core rod remains in an
extended position, up to the upper die face. The annular space left
by withdrawl of the annular punch is filled with powder or
granulate. At the next station, a core tablet is inserted onto the
tip of the core rod by conventional means, such as those used in
"press coat" machines like the Kilian RUD. The core tablet can be
positioned atop the core rod by any method. On further rotation,
the die comes to the compression station where the columnar punch
with, or without, its protrusion moves downward and pushes the core
tablet into the bed of powder or granular material. The force of
the columnar punch retracts the core rod against the bias and the
powder or granular material is compressed into an annular shape
around the core tablet. In the dosage form product, one recess is
defined by the height of the protrusion and the other recess is
defined by a combination of the factors such as the strength of the
bias, the fill depth, the compactability of the powder or granular
material and the thickness of the core tablet. After the powder is
compressed, the die rotates further to where the columnar punch is
withdrawn from the die. Either concurrently or subsequently, the
annular punch is raised until it reaches the die face. The core rod
rises concurrently to the die face due to the bias. The tablet is
swept out of the die by an ejection element and is collected.
[0073] While reference has been made to "upper" and "lower"
elements in the description of the toolset and process for making
solid dosage form according to the invention, the spacial
relationships of the elements are determined by the design and
construction of the press in which they are used. Use of the terms
"upper" and "lower" is not intended to limit the invention to a
vertical arrangement of the elements.
[0074] Having thus described the present invention with reference
to certain preferred embodiments, the invention will now be further
illustrated by the following example.
EXAMPLE
[0075] This example summarizes a study designed to determine the
rate and extent of absorption of alendronate sodium in human
subjects upon administration of a solid pharmaceutical dosage form
of the present invention ("protected tablet").
[0076] Materials and Methods
[0077] Protected tablets were made as follows.
[0078] Tablet Core: 85.4 g of alendronate trihydrate (TEVA Assia
Ltd.) and 2.6 g of xylitol (Danisco Sweeteners OY) were granulated
with 20 g water in a Diosna (model P1/6) granulator for 3 min. The
granulate was dried at 40.degree. C. for one hour in a fluidized
bed dryer and milled through a 0.8 mm screen. The granulate was
blended with 11 g crospovidone NF (BASF Pharma) for five minutes.
One gram magnesium stearate NF/EP (Mallinkrodt Inc.) was added and
the granulate was further blended for an additional 0.5 minutes.
The blend was compressed using a Manesty F3 single punch tablet
machine fitted with a 5 mm flat beveled punch. The tablet weight
was 94.9 mg.+-.1.0% RSD. The hardness of the core tablets was 3-6
kP.
[0079] Protected Tablets: A mixture of 94 grams compressible
sucrose (Nutab.TM., DMV International) and 5 grams microcrystalline
cellulose (Avicel.TM. pH102, FMC International) were blended for
five minutes. One gram magnesium stearate (NF/EP, Mallinkrodt Inc.)
was added and the mixture was blended for another half a
minute.
[0080] A Manesty f3 single punch tableting machine was fitted with
a spring-biased columnar punch and punch assembly constructed in
accordance with the present invention. The core rod was designed
for a 5 mm round core tablet and the die and punches for the outer
tablet were designed to produce a round, 9 mm diameter, flat
beveled solid pharmaceutical dosage form. The upper punch had a
protrusion of diameter 4.5 mm and 1.2 mm height. The tablet press
was operated and the protected tablets were produced. The tablet
weight was 474 mg.+-.0.62% RSD and the hardness of the protected
tablets was 12-15 kP. The alendronate trihydrate content, expressed
as alendronic acid was 66.8 mg.+-.1.38% RSD (82.4 mg alendronate
trihydrate being equivalent to 70 mg alendronic acid).
[0081] The drug-containing inner tablet was recessed from the
surface of the annular body by about 1 mm.
[0082] Pharmacokinetic Study
[0083] A clinical trial involving twelve (12) human volunteers was
conducted to demonstrate the pharmacokinetics of a solid dosage
form of the present invention containing 70 mg alendronate. Its
pharmacokinetics was compared to that of a commercial 70 mg
Fosalan.TM. tablet of the prior art (Merck, Sharpe &
Dohme).
[0084] Method
[0085] The study was a randomized, open-label, 2-treatment, 2
period, 2 sequence crossover design under fasting conditions.
Twelve (12) healthy adult male volunteers, 18-55 years of age were
the subjects in the study.
[0086] The study was divided into first and second study periods,
each of 36 hours duration, with a 14 day "wash-out" period between
the study periods. All subjects who completed both study periods
were included in the analysis. Subjects were randomly assigned to
two groups. One group was administered alendronate via the
protected tablet in the first period and administered control
Fosalan in the second period. The order of administration to the
second group was reversed.
[0087] In both periods, alendronate was administered in the fasted
state. A standardized meal was provided 4 hours after
administration. Snacks were provided on a standardized schedule
that was the same for all subjects in both study periods. Water was
provided ad libitum. In addition, subjects were encouraged to drink
at least 200 ml of water at regular intervals during each study
period.
[0088] The bioavailability of alendronate was determined by
measuring the cumulative levels of alendronate excreted in the
urine over a 36 hour period following oral ingestion of the test
and control tablets (hereafter "Ae.sub.0-36"). An initial (t=0)
urine sample was taken immediately after administration. Urine
samples were taken at 11 regularly scheduled points in time over
the 36 hour test period. All urine samples were analyzed for
alendronate using a validated HPLC-FLR assay.
[0089] Results
[0090] The main pharmacokinetic parameters obtained from the
analyses of urine samples are collected in Table 1.
1TABLE 1 Pharmacokinetic Parameters Administration via
Administration via Protected Tablet Fosalan (control) Parameter
Mean .+-.SD CV (%) Mean .+-.SD CV (%) Ae.sub.0-36 (.mu.g) 113.6
77.2 67.9 102.6 36.8 36.8 R.sub.max (.mu.g/h) 37.9 19.9 51.5 31.7
11.8 38.3 T.sub.max (h) 1.4 0.9 -- 1.4 0.9 --
[0091] A comparison of the pharmacokinetic parameters of the dosage
form in accordance with this invention with the pharmacokinetic
parameters of the prior art dosage form is provided in Table 2.
2TABLE 2 Comparison of Pharmacokinetics of the Protected Tablet to
Prior Art Ae.sub.0-36 (mg) R.sub.max (mg/h) Geometric Mean of Ratio
0.99 1.12 90% Geometric C.I. 75.31% to 128.79% 93.98% to 135.01%
Intra-subject C.V. 37.48% 24.85%
[0092] By reference to Tables 1 and 2, and FIG. 5, one can see that
alendronate administered via the solid dosage form of the present
invention gives essentially the same pharmacokinetic results as
administration via Fosalan. The total amount of the alendronate
excreted into urine over 36 hours is essentially the same for both
treatments with the maximum rates of excretion (parallel to
C.sub.max in a pharmacokinetic study of plasma levels of drug) also
close.
[0093] The profile of excretion into urine was similar for all
subjects and in both treatments. The majority of the subjects had
their maximum rate of excretion (R.sub.max) between one and two
hours. For five of the subjects, the R.sub.max occurred earlier
than 1 hour after administration when they took Fosalan. Four of
the subjects experienced a R.sub.max in less than an hour when they
took the protected tablet. One of the subjects had an R.sub.max in
the third hour when he took Fosalan while two of the subjects had a
R.sub.max in the third hour when they took the protected
tablet.
[0094] The total amount of excreted alendronate ranged from 36.9
.mu.g to 158.6 .mu.g when Fosalan was administered and from 30.1
.mu.g to 284.4 .mu.g when the solid oral dosage form of the present
invention was administered. In only two subjects was there a
greater than two fold difference between the total amount of
excreted alendronate between the two treatments. Another subject
excreted a very low amount of alendronate regardless of how the
alendronate was administered.
[0095] The bioavailability of alendronate administered via the
novel solid dosage form of the present invention in equivalent to
that of alendronate administered by dosage forms of the prior art.
However, the dosage form of the prior art does not provide any
protection against contact of the alendronate with the mucous
membranes of the esophageous and stomach while the bioequivalent
novel dosage form of the present invention affords such
protection.
[0096] Having thus described the invention with reference to
certain preferred embodiments, other embodiments will be apparent
from this description to those skilled in the art to which the
invention pertains. It is intended that the specification is
considered exemplary only, with the scope and spirit of the
invention being indicated by the claims which follow.
* * * * *