I 1111111111111111 11111 111111111111111 111111111111111 111111111111111 IIII IIII
`US007704977B2
`
`c12) United States Patent
`Leonard
`
`(IO) Patent No.:
`(45) Date of Patent:
`
`US 7,704,977 B2
`Apr. 27, 2010
`
`(54) SOLID ORAL DOSAGE FORM CONTAINING
`AN ENHANCER
`
`(75)
`
`Inventor: Thomas W. I. Leonard, Wilmington,
`NC (US)
`
`(73) Assignee: Merrion Research III Limited, Dublin
`(IE)
`
`( *) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 112 days.
`
`(21) Appl. No.: 11/733,007
`
`(22) Filed:
`
`Apr. 9, 2007
`
`(65)
`
`Prior Publication Data
`
`US 2007 /0238707 Al
`
`Oct. 11, 2007
`
`Related U.S. Application Data
`
`(60) Provisional application No. 60/791,231, filed on Apr.
`7, 2006.
`
`(51)
`
`Int. Cl.
`A61K 311675
`(2006.01)
`A61K 31/663
`(2006.01)
`A61K 31/20
`(2006.01)
`A61K 9/48
`(2006.01)
`(52) U.S. Cl. ......................... 514/89; 514/102; 514/558;
`424/451
`(58) Field of Classification Search ................. 424/451;
`514/89, 102, 558
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
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`Anderberg et al. "Sodium Caprate Effects Dilations in Human Intes(cid:173)
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`
`(Continued)
`
`Primary Examiner-Humera N Sheikh
`Assistant Examiner-Aradhana Sasan
`(74) Attorney, Agent, or Firm-Myers Bigel Sibley &
`Sajovec P.A.
`
`(57)
`
`ABSTRACT
`
`The invention relates to a pharmaceutical composition and
`oral dosage forms comprising a bisphosphonate in combina(cid:173)
`tion with an enhancer to enhance intestinal delivery of the
`bisphosphonate to the underlying circulation. Preferably, the
`enhancer is a medium chain fatty acid or a medium chain fatty
`acid derivative having a carbon chain length of from 6 to 20
`carbon atoms, and the solid oral dosage form is a controlled
`release dosage form such as a delayed release dosage form.
`
`34 Claims, 17 Drawing Sheets
`
`Mean Plot
`
`0.30
`
`1 0.25
`ii 0.20
`8 i' 0.15
`i 0.10
`JI
`< 0.05
`
`Bloatudy 0601001
`Human Alendronate Study
`MEAN PLOT
`
`-----e----------··-'
`
`12
`
`18
`
`20
`
`Tlme_(h)
`
`24
`
`28
`
`32
`
`36
`
`-E>- Trt A -351ll(! Fosamax Fasted (PO)
`-e- Trt 8 • 17.Smg Alendronate +0.Sg C10 ae 2 tablets Fasted (PO)
`+ TrtC • 17.Slll(! Alendronate + 0.5g 010 ae 2tablets Fed (PO)
`
`+ Trt D • 17 .5mg Alendronate + 0.25g C10 as 2 tablets Fasted (PO)
`.,.. Trt E • 17.Smg Alendronate + 0.25g C10 as 1 tablet Fasted (PO)
`
`

`

`US 7,704,977 B2
`Page 2
`
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`
`

`

`US 7,704,977 B2
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`* cited by examiner
`
`

`

`U.S. Patent
`U.S. Patent
`
`Apr. 27, 2010
`Apr. 27, 2010
`
`Sheet 1 of 17
`Sheet 1 of 17
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`U.S. Patent
`
`Apr. 27, 2010
`
`Sheet 6 of 17
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`US 7,704,977 B2
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`

`

`U.S. Patent
`
`Apr. 27, 2010
`
`Sheet 7 of 17
`
`US 7,704,977 B2
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`

`

`U.S. Patent
`
`Apr. 27, 2010
`
`Sheet 9 of 17
`
`US 7,704,977 B2
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`

`

`U.S. Patent
`
`Apr. 27, 2010
`
`Sheet 11 of 17
`
`US 7,704,977 B2
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`

`U.S. Patent
`U.S. Patent
`
`Apr. 27, 2010
`Apr. 27, 2010
`
`Sheet 12 of 17
`Sheet 12 of 17
`<l'. m o
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`US 7,704,977 B2
`US 7,704,977 B2
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`

`U.S. Patent
`U.S. Patent
`
`Apr. 27, 2010
`Apr. 27, 2010
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`

`Mean Plot
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`a.so I
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`Blostudy 0601001
`Human Alendronate Study
`MEAN PLOT
`
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`
`d r.,;_
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`
`

`

`U.S. Patent
`
`Apr. 27, 2010
`
`Sheet 17 of 17
`
`US 7,704,977 B2
`
`Figure 17
`
`l.EAST-SOUI\RES MOO CUMUlATIVE ZOLEDRONIC AClO EXCRETION IN URINE {N=12)
`
`0.6....-----------------------------,
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`24
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`

`

`US 7,704,977 B2
`
`1
`SOLID ORAL DOSAGE FORM CONTAINING
`AN ENHANCER
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`This application is based on and claims priority to U.S.
`Provisional Application No. 60/791,231, filed Apr. 7, 2006,
`the contents of which are fully incorporated herein by refer(cid:173)
`ence.
`
`FIELD OF THE INVENTION
`
`The present invention relates to a compositions and solid
`oral dosage forms containing an enhancer. In particular the
`invention relates to compositions and solid oral dosage forms
`comprising a pharmaceutically active ingredient in combina(cid:173)
`tion with an enhancer which enhances the bioavailability
`and/or the absorption of the active ingredient.
`
`BACKGROUND OF THE INVENTION
`
`The epithelial cells lining the lumenal side of the gas(cid:173)
`trointestinal tract (GIT) can be a major barrier to drug delivery
`via oral administration. However, there are four recognized
`transport pathways which can be exploited to facilitate drug
`delivery and transport: the transcellular, paracellular, carrier(cid:173)
`mediated and transcytotic transport pathways. The ability of
`a drug, such as a conventional drug, a peptide, a protein, a
`macromolecule or a nano- or microparticulate system, to
`"interact" with one or more of these transport pathways may
`result in increased delivery of that drug from the GIT to the
`underlying circulation.
`Certain drugs utilize transport systems for nutrients which 35
`are located in the apical cell membranes ( carrier mediated
`route). Macromolecules may also be transported across the
`cells in endocytosed vesicles (transcytosis route). However,
`many drugs are transported across the intestinal epithelium
`by passive diffusion either through cells (transcellular route)
`or between cells (paracellular). Most orally administered
`drugs are absorbed by passive transport. Drugs which are
`lipophilic permeate the epithelium by the transcellular route
`whereas drugs that are hydrophilic are restricted to the para(cid:173)
`cellular route.
`Paracellular pathways occupy less than 0.1 % of the total
`surface area of the intestinal epithelium. Further, tight junc(cid:173)
`tions, which form a continuous belt around the apical part of
`the cells, restrict permeation between the cells by creating a
`seal between adjacent cells. Thus, oral absorption of hydro- 50
`philic drugs such as peptides can be severely restricted. Other
`barriers to absorption of drugs may include hydrolyzing
`enzymes in the lumen brush border or in the intestinal epithe(cid:173)
`lial cells, the existence of the aqueous boundary layer on the
`surface of the epithelial membrane which may provide an 55
`additional diffusion barrier, the mucus layer associated with
`the aqueous boundary layer and the acid microclimate which
`creates a proton gradient across the apical membrane.
`Absorption, and ultimately bioavailability, of a drug may also
`be reduced by other processes such as P-glycoprotein regu- 60
`lated transport of the drug back into the gut lumen and cyto(cid:173)
`chrome P450 metabolism. The presence of food and/or bev(cid:173)
`erages can also interfere with absorption and bioavailability.
`Bisphosphonates are a family of drugs used to prevent and
`treat bone fractures, osteoporosis, Paget's disease, metastatic 65
`bone cancer, and other bone diseases with high bone resorp(cid:173)
`tion. Bisphosphonates bind to bone hydroxyapatite and slow
`
`20
`
`2
`down bone-eroding cells known as osteoclasts. This effect
`allows the bone-building cells known as osteoblasts to work
`more effectively.
`Some of the limitations with conventional bisphospho-
`5 nates include irritation of the upper GIT, such as esophageal
`ulcers, and low bioavailability. As a result, conventional bis(cid:173)
`phosphonates require a specific dosing regimen so that the
`patient can absorb some of the drug properly and avoid side
`effects. Because foods, beverages, medications and calcium
`10 interfere with absorption, conventional bisphosphonates
`must be administered on an empty stomach and, depending
`on the particular bisphosphonate, must wait from 30 minutes
`to two hours before consuming any food, beverages ( other
`than water), medications or calcium supplements. As esoph-
`15 ageal ulcers are a known side effect, dosing regimens for
`conventional bisphosphonates specify that patients consume
`an entire glass of water with the dosage form and avoid
`assuming a horizontal orientation, such as by lying down,
`within 30 to 60 minutes after administration.
`The specific characteristics of alendronate served to exem-
`plify the members of the class of bisphosphonates and the
`issues associated with them. Alendronate is a white, crystal(cid:173)
`line, odorless, non-hygroscopic bisphosphonate prepared by
`chemical synthesis. Alendronate monosodium trihydrate has
`25 a molecular weight of325.1. Alendronate is approved in the
`U.S. for the prevention and treatment of osteoporosis in men
`and postmenopausal women, and for the treatment of Paget' s
`disease of bone and glucocorticoid induced osteoporosis in
`both sexes. Like other bisphosphonates, alendronate binds to
`30 bone hydroxyapatite and specifically inhibits the activity of
`osteoclasts. Alendronate reduces bone turnover in human and
`animal models and decreases activation frequency, reducing
`bone resorption in both cortical and trabecular bone and ulti-
`mately increasing bone density and strength.
`The oral bioavailability of alendronate is very low and
`independent of the dose (5-80 mg), averaging 0.76% in
`women and 0.59% in men. Presystemic metabolism does not
`occur. Following oral administration of conventional forms of
`alendronate, 40% of the dose absorbed is excreted in the urine
`40 within 8 hours and a further 5% is excreted over the next 64
`hours. Sixty to seventy percent of the absorption occurs
`within 1 hour of dosing. Bioavailability is markedly reduced
`by coincident consumption of food (85%-90%) and even
`consumption of coffee or orange juice will impair absorption
`45 by as much as 60% or more. Coincident medication will also
`reduce absorption, as any calcium-containing compounds
`and multivalent cations will bind to the bisphosphonate.
`Elevation of gastric pH above 6 is associated with a twofold
`increase in alendronate absorption. Alendronate is not
`metabolized and is excreted unchanged with renal clearance
`comparable to the glomerular filtration rate.
`Bisphosphonate compositions and oral dosage forms with
`improved systemic bioavailability which are not subject to
`the dosing restrictions of conventional bisphosphonates
`would represent a considerable benefit for patients. As a
`result, new strategies for delivering drugs across the GIT cell
`layers are needed, particularly for bisphosphonates.
`Numerous potential absorption enhancers have been iden(cid:173)
`tified. For instance, medium chain glycerides have demon(cid:173)
`strated the ability to enhance the absorption of hydrophilic
`drugs across the intestinal mucosa (Phann. Res. (1994), 11,
`1148-54). However, the importance of chain length and/or
`composition is unclear and therefore their mechanism of
`action remains largely unknown. Sodium caprate has been
`reported to enhance intestinal and colonic drug absorption by
`the paracellular route (Pharm. Res. (1993) 10, 857-864;
`Pharm. Res. (1988), 5, 341-346). U.S. Pat. No. 4,656,161
`
`

`

`US 7,704,977 B2
`
`4
`According to another aspect of the present invention, the
`compositions and dosage forms made therefrom comprise a
`drug and an enhancer to promote absorption of the bisphos(cid:173)
`phonate at the GIT cell lining, wherein the only enhancer
`5 present in the composition is a medium chain fatty acid or a
`medium chain fatty acid derivative having a carbon chain
`length of from 6 to 20 carbon atoms.
`In embodiments in which the drug comprises a bisphos(cid:173)
`phonate, the drug may be selected from the group that
`10 includes the free acids forms and biologically acceptable salts
`of alendronate, clodronate, etidronate, incadronate, ibandr(cid:173)
`onate, minodronate, neridronate, olpadronate, pamidronate,
`risedronate, tiludronate, zoledronate and derivatives thereof.
`The bisphosphonate dosage form may be an enteric coated
`15 instant release solid oral dosage form which provides
`improved oral bioavailability and minimizes the risk oflocal
`irritation of the upper GIT. In one embodiment, the bisphos(cid:173)
`phonate is zoledronic acid.
`The dosage forms can be a tablet, a multiparticulate or a
`20 capsule. The multi particulate can be in the form of a tablet or
`contained in a capsule. The tablet can be a single or multilayer
`tablet having compressed multi particulate in one, all or none
`of the layers. Preferably, the dosage form is a controlled
`release dosage form. More preferably, it is a delayed release
`25 dosage form. The dosage form can be coated with a polymer,
`preferably a rate-controlling or a delayed release polymer.
`The polymer can also be compressed with the enhancer and
`drug to form a matrix dosage form such as a controlled release
`matrix dosage form. A polymer coating can then be applied to
`30 the matrix dosage form.
`Other embodiments of the invention include the process of
`making the dosage forms, and methods for the treatment of a
`medical condition by administering the dosage forms to a
`patient and use of a drug and enhancer in the manufacture of
`35 a medicament.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`3
`(BASF AG) discloses a process for increasing the enteral
`absorbability of heparin andheparinoids by adding non-ionic
`surfactants such as those that can be prepared by reacting
`ethylene oxide with a fatty acid, a fatty alcohol, an alkylphe(cid:173)
`nol or a sorbitan or glycerol fatty acid ester.
`U.S. Pat. No. 5,229,130 (Cygnus Therapeutics Systems)
`discloses a composition which increases the permeability of
`skin to a transdermally administered pharmacologically
`active agent formulated with one or more vegetable oils as
`skin permeation enhancers. Dermal penetration is also known
`to be enhanced by a range of sodium carboxylates [Int. J. of
`Pharmaceutics (1994), 108, 141-148]. Additionally, the use
`of essential oils to enhance bioavailability is known (U.S. Pat.
`No. 5,66,386 AvMax Inc. and others). It is taught that the
`essential oils act to reduce either, or both, cytochrome P450
`metabolism and P-glycoprotein regulated transport of the
`drug out of the blood stream back into the gut.
`Often, however, the enhancement of drug absorption cor(cid:173)
`relates with damage to the intestinal wall. Consequently, limi(cid:173)
`tations to the widespread use of GIT enhancers are frequently
`determined by their potential toxicities and side effects.Addi(cid:173)
`tionally and especially with respect to peptide, protein or
`macromolecular drugs, the "interaction" of the GIT enhancer
`with one of the transport pathways should be transient or
`reversible, such as a transient interaction with or opening of
`tight junctions so as to enhance transport via the paracellular
`route.
`As mentioned above, numerous potential enhancers are
`known. However, this has not led to a corresponding number
`of products incorporating enhancers. One such product cur(cid:173)
`rently approved for use in Sweden and Ja