EP1594496A2 - Novel therapeutic method and compositions for topical administration - Google Patents
Novel therapeutic method and compositions for topical administrationInfo
- Publication number
- EP1594496A2 EP1594496A2 EP04711191A EP04711191A EP1594496A2 EP 1594496 A2 EP1594496 A2 EP 1594496A2 EP 04711191 A EP04711191 A EP 04711191A EP 04711191 A EP04711191 A EP 04711191A EP 1594496 A2 EP1594496 A2 EP 1594496A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- skin
- nominal flux
- photoageing
- drug substance
- flux
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/10—Anti-acne agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
Definitions
- This invention relates to a novel therapeutic method employing farglitazar, in particular to a method of treatment of diseases associated with the skin and to pharmaceutical compositions and their use in such method.
- thiazolidinediones e.g. U.S. Pat Nos. 5,089,514, 4,342,771 , 4,367,234, 4,340,605, 5,306,726
- NIDDM non insulin dependent diabetes mellitus
- the thiazolidinedione troglitazone was shown to have these same beneficial effects in human patients suffering from impaired glucose tolerance, a metabolic condition that precedes the development of NIDDM, as in patients suffering from NIDDM (J. J. Nolan et.
- Thiazolidinediones also induce the in vitro differentiation of preadipocyte cell lines into mature adipocytes (A. Hiragun, et. al. J. Cell. Physiol. 124-130, 134 (1988); R. F. Kleitzen, et. al., Mol. Pharmacol. 393-398, 41 (1992)).
- Treatment of preadipocyte cell lines with the thiazolidinedione pioglitazone results in increased expression of the adipocyte-specific genes aP2 and adipsin as well as the glucose transporter proteins GLUT-1 and GLUT-4, which suggests that the hypoglycaemic effects of thiazolidinediones seen in vivo may be mediated through adipose tissue.
- PPAR-gamma Peroxisome Proliferator- Activated Receptor gamma
- PPAR-gamma Peroxisome Proliferator- Activated Receptor gamma
- PPAR-alpha Three mammalian PPARs have been isolated and termed PPAR-alpha, PPAR-gamma, and NUC-1 , or PPAR ⁇ . These PPARs regulate expression of target genes by binding to DNA sequence elements, termed PPAR response elements (PPRE).
- PPRE PPAR response elements
- PPRE's have been identified in the enhancers of a number of genes encoding proteins that regulate lipid metabolism suggesting that PPARs play a pivotal role in the adipogenic signaling cascade and lipid homeostasis (H. Keller and W. Wahli, Trends Endocrin. Met. 291- 296, 4 (1993)).
- Thiazolidinediones are now known to be potent and selective activators of PPAR-gamma and bind directly to the PPAR-gamma receptor (J. M. Lehmann et. al., J. Blol. Chem. 12953-12956, 270 (1995)), providing evidence that PPAR-gamma is a possible target for the therapeutic actions of the thiazolidinediones. Indeed, since PPAR-gamma was identified as a key molecular target for thiazolidinediones, this nuclear transcription factor has been identified in a large number of human cell types, and thiazolidinediones have been claimed to have a broad spectrum of potential clinical utilities, for example in certain forms of cancer (e.g.
- thiazolidinediones can modulate the functions of white blood blood cells (e.g. R. Garg et al, Hypertension 430-435, 36 (2000); N. Marx et al, Circ. Res. 703-710, 90 (2002)) as well as reduce their number in the circulation (S.M. Haffner et al, Circulation 679- 684, 106 (2002)).
- European Patent 306228 describes a class of PPAR gamma agonists which are thiazolidinedione derivatives for use as insulin sensitisers in the treatment of Type II diabetes m ⁇ llitus. These compounds have anti-hyperglycaemic activity.
- One preferred compound described therein is known by the chemical name 5-[4-[2 ⁇ (N- methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione and has been given the generic name rosiglitazone. Salts of this compound including the maleate salt are described in WO94/05659.
- One such compound has chemical name N-(2- benzoylphenyl)-O-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-L-tyrosine (also known as 2(S)-(2-benzoyl-phenylamino)-3- ⁇ 4-[2-5- methyl- 2-phenyl-oxazol-4-yl)-ethoxy]- phenylj-propionic acid, or by the generic name farglitazar, or by the registry number GI262570).
- a method of synthesising farglitazar is shown in Example 29.
- US Patent 5,594,015 (Kurtz et al) describes the use of certain thiazolidinedione derivatives including pioglitazone and ciglitazone for the treatment of psoriasis through a mechanism involving inhibition of proliferation of keralinocytes.
- This patent describes a range of presentations by which the drug substance may be administered to the patient, including, for example, by applying a cream or oil of around 1-2% strength directly to the psoriatic lesion, or by administering the medication orally.
- US Patent 6,403,656 (Rivier et al) reports similar findings to those of Kurtz, together with the observation that the level of expression of PPAR gamma in psoriatic lesions is reduced relative to the healthy state.
- This patent describes the use of PPAR gamma agonists including thiazolidinediones as well as certain tyrosine derivatives in the treatment of abnormalities of differentiation in epidermal cells, more particularly in the treatment of psoriasis, atopic dermatitis and eczema, acne, light induced keratosis and skin cancers.
- the compounds are indicated for oral, topical and parenteral administration, for example by the topical route in the form of pasty ointments, creams, milks, creamy ointments, powders, impregnated pads, solutions, gels, sprays, lotions or suspensions typically at a concentration of 0.001 -10% preferably 0.01 -1 % by weight based on weight of composition.
- Neither Kurtz nor Rivier discuss how to achieve an anti-psoriatic effect without at the same time causing an unwanted anti- hyperglycaemic effect.
- Topical delivery of drugs provides a key advantage over systemic drug delivery as, ideally, the pharmacological effects of the drug administered will occur only locally and not systemically as plasma concentration will be too low to allow the drug to induce any pharmacological effect. This therefore offers the potential advantage of providing a larger therapeutic window with topical therapy than with systemic therapy.
- drugs Due to the absence of a manner of intelligently pre-selecting the desired dosage, and the need to be cautious in the performance of clinical trials which results in a tendency to under-dose, many drugs fail to achieve their therapeutic potential.
- Some drugs such as PPAR gamma agonists, are capable of exhibiting a number of different therapeutic effects some of which will be desired and some of which will not be desired in a given clinical situation. For example one therapeutic effect may arise when the drug is administered topically and another when administered systemically. Thus there is needed a method of achieving the desired therapeutic effect without the undesired one.
- compositions According to the classical way of describing pharmaceutical compositions, whether they be oral or topical preparations, it is primarily the amount of drug present in these pharmaceutical compositions which is used to characterise the composition.
- the amount in the dose given is usually a good indicator of the dose absorbed and therefore of the plasma concentration.
- Variation in plasma levels achieved after the dosing of the same drug in two different oral preparations is usually small.
- the amount of drug present in the preparation is classically used to describe the preparation, as for oral preparations, and is usually expressed as the percentage of drug in the preparation.
- the variability in the amount absorbed is large compared to oral dosage forms as the bioavailability of topical drugs is generally low. This variability can be of one or two orders of magnitude depending on the excipients used in the preparation.
- a pharmaceutical composition suitable for topical administration to the skin which comprises farglitazar, or a pharmaceutically acceptable salt thereof, and a physiologically acceptable carrier.
- a pharmaceutical composition suitable for topical administration to the skin which comprises farglitazar, or a pharmaceutically acceptable salt thereof, and a physiologically acceptable carrier.
- a formulation in the topical treatment of a skin condition such as psoriasis, atopic dermatitis, facial acne, rosacea, photoageing of the face, photoageing of the hands or skin cancer.
- farglitazar or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the topical treatment of a skin condition such as psoriasis, atopic dermatitis, facial acne, rosacea, photoageing of the face, photoageing of the hands or skin cancer
- a skin condition such as psoriasis, atopic dermatitis, facial acne, rosacea, photoageing of the face, photoageing of the hands or skin cancer
- the window is bounded at the upper end by a flux that is sufficiently low that it does not result in any undesired systemic pharmacological effect and is bounded at the lower end by a flux that is sufficiently high that it leads to a desired local pharmacological effect.
- the stratum comeum (SC) or horny layer is the outermost layer of the skin and the main barrier to percutaneous absorption of chemical compounds despite being a very thin layer of an average thickness of 10-20 ⁇ m.
- the barrier properties of the SC are attributed to the highly organised layers of flattened, polygonal corneocytes and specialised intercellular lipids.
- the corneocytes are cell remnants of the terminally differentiated keratinocytes found in the basal layer of the epidermis at the epidermal- dermal junction.
- the corneocytes are surrounded by a practically insoluble and very resistant cell envelope.
- the intercellular space is filled with lipids organised in stacked bilamellar structures sandwich with a continuous water phase.
- the lipids located in the intercellular space play a key role in the barrier formation.
- the viable epidermis constitutes a dynamic system in which the keratinocytes, proliferated from the basal layer, differentiate as they progress towards the SC and get transformed into corneocytes.
- the turnover time for a keratinocyte from the basal layer to the skin surface is about 28 days for normal skin. It also contains specialised cells like melanocytes, which protect the body against UV radiation.
- the viable epidermis does not contain blood vessels as it receives nourishment from the dermis by passive diffusion. The viable epidermis is not considered as having strong barrier properties.
- the dermis is situated below the viable epidermis. It is approximately 1 to 3 mm thick and makes the bulk of the skin. It consists of a matrix of connective tissue made from fibrous proteins like elastin and collagen.
- the main functions of the dermis are to give mechanical strength and elasticity to the skin barrier, to supply oxygen and nutrients, and to remove waste products.
- the dermis has an extensive vascular supply, which regulates temperature and pressure, delivers nutrients, removes waste products and mobilises defence forces.
- Terminal hair follicles e.g. hair on the head
- a large hair is associated with a large sebaceous gland.
- the root of this hair may extend more than 3mm below the skin surface into the subcutaneous fatty tissue.
- Vellus hair follicles e.g. fine hairs on the face in women
- its roots extend less than 1 mm in the dermis.
- Sebaceous follicles (or sebaceous gland follicles), characteristics of human beings and not present in animals. They are found mainly on the face and the central parts of chest and back. It consists of 4 parts: the sebaceous gland lobes that secretes sebum (a mixture of lipids), the sebaceous ducts that connects the lobes and the secretory duct, a small vellus hair and the secretory duct which is a long duct lined by keratinocytes that is the large conducting duct that conducts the sebum coming from the sebaceous gland to the skin surface. The keratinocytes produce corneocytes which normally are ejected outwards. The sebaceous duct is situated approximately 0.5 mm below the skin surface.
- the sweat glands are found mainly on the face and the central parts of chest and back. It consists of 4 parts: the sebaceous gland lobes that secretes sebum (a mixture of
- Sweat glands are tubular glands distributed almost over the entire human body. Each gland has a secretory part located below the dermis in the subcutaneous tissue and an excretory duct that ultimately opens directly on the skin surface. These glands produce perspiration.
- a number of skin conditions may desirably be treated by topical administration of an active drug substance. For example:
- Psoriasis is an inflammatory skin condition which has been described in J Invest Dermatol (1983) 81 503-506 and J Amer Acad Dermatol (1983) 8(5) 645-647.
- the psoriatic skin lesions are inflammatory, red, sharply delimited plaques of various shapes with characteristics silvery lustrous scaling.
- the second one occurs in the dermis where there is a strong inflammatory reaction coupled with a network of capillaries expanding from the one present in normal skin (this is called angiogenesis)
- angiogenesis a network of capillaries expanding from the one present in normal skin
- the target layer of the skin is usually both the bottom of the epidermis and the top of the dermis.
- both the bottom of the epidermis and the top of the dermis are considered the target sites for the drug's effect, as such drugs can affect (a) the differentiation/proliferation of keratinocytes process (bottom of epidermis), (b) the inflammatory process (top of dermis), and (c) the angiogenesis process (top of dermis).
- Atopic dermatitis is an inflammatory skin condition which has been described in J Invest Dermatol (1982) 79 243-245, Br J Dermatol (1988) 118, 517-522, J Am Acad Dermatol (1995) 33, 969-972 and J Dermatol Sci (2000) 23, 178-182 - "Atopic Dermatitis: From Pathogenesis to treatment" - author/editor Leung D.Y.M. - 1996 - Springer-Verlag .
- Atopic dermatitis is the most common form of dermatitis and is a chronic inflammatory skin condition whose classic feature is itchy skin. The great majority of cases occur in infancy and childhood.
- the skin is dry, flaky, rough, and can be secondarily infected and show oozing and crusts.
- the skin barrier property of atopic dermatitis lesions is viewed as being down compared to normal.
- the main treatment skin tissue target for this disease is the top layer of the dermis where the inflammation occurs.
- the top of the dermis is considered the target for the drug's effect, as such drugs can affect the inflammatory process (top of dermis).
- Facial acne is one of the most common diseases in dermatology. It occurs at puberty in almost every one, although to different extents and regresses in early adulthood. The preferred sites are naturally on the face as this is a disease affecting the sebaceous follicles. It is characterised by seborrhoea, disturbed keratinisation in the follicles with comedones and subsequent inflammatory papules, pustules, and nodular abscesses and scars.
- seborrhoea disturbed keratinisation in the follicles with comedones and subsequent inflammatory papules, pustules, and nodular abscesses and scars.
- One of the most important factors in acne is the superior production of sebum in acne sites as opposed to healthy skin sites. Sebaceous follicles are densely populated by bacteria and fungi.
- propionibacteria In the deeper anaerobic area of the sebaceous glands one finds propionibacteria. These produce lipases and are regarded as a substantial factors in the pathogenesis of acne.
- the first detectable sign of acne is increased production of corneocytes in the secretory duct, but these are no longer extruded outwards.
- Comedones blockage of the sebaceous follicle
- Bacteria proliferation and inflammation can then occur [Braun-Falco O., Plewig G., Wolff H.H. & Winkelmann R.K.
- the whole dermis is considered the target for the drug's effect, as such drugs can affect (a) the differentiation/proliferation of keratinocyte that cover the wall of the sebaceous ducts, which ducts run down into the dermis (whole dermis), (b) the inflammatory process that occurs around the sebaceous gland (whole dermis), and (c) the excess sebum production (on the external surface of sebocyte gland) (whole dermis).
- Rosacea is a condition having as a classic symptoms a persistent flushing of the face, leading to a polymorphic picture of persistent redness, papules, telangiectasia, thickening and coarsening of the skin and in its most extreme form gross enlargement and deformity of the nose.
- the areas most characteristically affected are the central convex areas of the face (nose, forehead, cheeks and chin), although the scalp, upper chest, back and even the limbs may be involved.
- the onset of rosacea is preceded by episodic flushing unaccompanied by sweating, these attacks being readily triggered by local stimuli including hot drinks, spicy food, alcohol, excessive sunlight and emotion.
- Erythema which is accompanied by a burning sensation, gradually becomes more persistent and is associated with increasingly prominent telangiectasia. More advanced stages show follicular and non-follicular papules and pustules without comedones followed by persistent tissue thickening due to oedema leading ultimately to a punished d'orange appearance and rhinophyma. Untreated, rosacea becomes slowly but inexorably more severe, although there may be temporary remissions and severe relapses on the way depending on the exposure to or withdrawal of exacerbating factors.
- the top of the dermis is considered as a target site for the drug's effect, as such drugs can affect (a) the inflammatory process (top of dermis), and (b) the angiogenesis process (top of dermis).
- Skin Photoageing is the gradual deterioration of cutaneous structure and function following long term, recurrent exposure to sunlight or artificial UVR sources. It apparently occurs as a result of cumulative DNA damage resulting from recurrent, acute DNA injury and from the effects of chronic inflammation. Epidermis and dermis are both affected by UVB and the dermis is significantly affected by UVA as well.
- the whole dermis is considered as the target site for the drug's effect, as such drugs can affect (a) the differentiation/proliferation of the poorly differentiated cells of the dermis (whole dermis), (b) the inflammatory process (top of dermis), (c) the production of collagen break down product (whole dermis) and (d) the Retinoid X Receptors (whole dermis).
- Skin cancer can be present in many forms that can affect all the viable skin tissues (epidermis, dermis or appendages). The different forms can be benigm or malignant tumours.
- the target site is therefore the whole depth of the skin viable tissue, ranging from the epidermis to the bottom of the dermis.
- the bottom of the epidermis as well as the whole dermis are considered as the target site for the drug's effect, as such drugs can affect (a) the differentiation/proliferation of skin cells [melanocytes in particular] (bottom of epidermis and whole dermis) and (b) the angiogenesis process (top of dermis).
- a method for treating a skin condition selected from the list consisting of psoriasis, atopic dermatitis, facial acne, rosacea, photoageing of the face, photoageing of the hands and skin cancer which comprises administering topically to the skin of a patient in need of treatment a pharmaceutical composition containing a drug substance which is farglitazar or a pharmaceutically acceptable salt thereof characterised in that the formulation delivers to the skin a nominal flux of said drug substance which is greater than the minimum nominal flux required to cause a therapeutic effect against the skin condition (hereinafter “lower limit nominal flux”) and less than the minimum nominal flux which will cause a systemic anti-hyperglycaemic effect (hereinafter “upper limit nominal flux”).
- the minimum nominal flux which will cause a systemic anti-hyperglycaemic effect (“upper limit nominal flux”) is defined in this invention as the flux which results in a peak plasma concentration which is comparable with (for example the same as or within around 20%, ideally the same as) that obtained by administering farglitazar with a therapeutic dose by the oral route ("oral therapeutic dose").
- An oral therapeutic dose is defined as a dose that would lead to a substantial systemic anti-hyperglycaemic effect if dosed to a patient suffering from Type II diabetes mellitus or another condition alleviated by insulin sensitivity enhancement.
- the method is not limited to the treatment of patients suffering from such conditions.
- compositions containing a drug substance which is farglitazar or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the topical treatment to the skin of a patient suffering from a skin condition selected from the list consisting of psoriasis, atopic dermatitis, facial acne, rosacea, photoageing of the face, photoageing of the hands, and skin cancer characterised in that the composition delivers to the skin a nominal flux of said drug substance which is greater than the minimum nominal flux required to cause a therapeutic effect against the skin condition and less than the minimum nominal flux which will cause a systemic anti-hyperglycaemic effect.
- the lower limit nominal flux and the upper limit nominal flux are respectively given (expressed in units of ng/cm 2 /hr) by equations (1 ) and (2) as follows:
- equation (1) in the case of psoriasis equation (1) is: Z / 2.4 and equation (2) is: Z * C / [200 * (100-PBF)]
- equation (1) in the case of photoageing of the hands equation (1) is: Z / 4 and equation (2) is: Z * C * / [40 * (100-PBF)]
- Z is expressed in units of ng/ml and is the target local free (i.e. unbound) concentration that is expected to have a therapeutic effect against the skin condition.
- Z should correspond to the peak plasma free drug concentration generated by dosing these drugs orally to treat effectively Type II diabetes mellitus.
- the appropriate value of Z may be determined experimentally in vivo by conventional known means using standard protocols.
- C is expressed in units of ml/hr and is the rate of clearance of the drug substance. Clearance may be determined experimentally in vivo by conventional known means using standard tests. For example it can be determined from the plasma concentration in response to a defined input of drug using the equation given below:
- Plasma bound fraction is the plasma bound fraction. Plasma bound fraction may be determined experimentally in vitro by conventional known means using standard tests (preferably a method employing equilibrium dialysis).
- nominal flux is meant the flux that passes through healthy skin in a healthy individual (i.e. not diseased skin) on a body site such as the trunk, abdomen, legs, back, arms (but not the face), especially the back, averaged over a 24 hour period.
- the equations take account of the different barrier and clearance properties of skin in disease conditions and on the face (for example the skin of the face is approximately 5 times more permeable than the skin of other parts of the body).
- the nominal flux of a given composition may be determined by an in vivo measurement or may be estimated using an in vitro measurement using the tests given below.
- the nominal flux is a flux averaged over a 24 hr period it follows that the flux may be achieved through use of any suitable dose regimen (for example application a number of times per day, eg twice per day, or application every other day). It is expected that the same formulation will be applied on each treatment, although this is not required and, for example, one formulation could be applied at one time in the day and another formulation at another time in the day. In the event that the calculated figure for Equation (2) is less than that for
- Equation (1) then the drug substance in question is not suitable for use in the method.
- the equations therefore reduce the needed flux only to consideration of three variables, defined above and labelled Z (a measure of intrinsic therapeutic activity), C (clearance) and PBF (a measure of availability of free drug).
- Z a measure of intrinsic therapeutic activity
- C clearance
- PBF a measure of availability of free drug
- the lower limit nominal flux is 10/3 times greater than the minimum nominal flux required to cause a therapeutic effect against the skin condition.
- the upper limit nominal flux is one-fifth of the maximum nominal flux which will cause a systemic anti-hyperglycaemic effect.
- the lower limit nominal flux is 10/3 times than that given above in equations (1).
- the upper limit nominal flux is one fifth of that given above in equations (2).
- the drug is farglitazar. It will be understood that farglitazar may be employed as a pharmaceutical acceptable salt eg the sodium salt, however weights given herein are calculated based on farglitazar free acid.
- the value Z for farglitazar is 0.31 ng/ml [Peak plasma concentration for a 5mg dose is about 157 ng/ml; 0.31 is 157*(100-99.8)/100].
- the clearance of farglitazar is 15000 ml/hr (in adults)
- the plasma bound fraction of farglitazar is 99.8%
- the oral therapeutic dose for farglitazar is 2.5mg in a single dose or two divided doses per day.
- a method for treating a skin condition selected from the list consisting of psoriasis, atopic dermatitis, facial acne, rosacea, photoageing of the face, photoageing of the hands and skin cancer which comprises administering topically to the skin of a patient in need of treatment a pharmaceutical composition containing a farglitazar or a pharmaceutically acceptable salt thereof characterised in that the formulation delivers a nominal flux of farglitazar to the skin which is greater than A and less than B where A and B are as follows:
- a method for treating a skin condition selected from the list consisting of psoriasis, atopic dermatitis, facial acne, rosacea, photoageing of the face, photoageing of the hands and skin cancer which comprises administering topically to the skin of a patient in need of treatment a pharmaceutical composition containing a farglitazar or a pharmaceutically acceptable salt thereof characterised in that the formulation delivers a nominal flux of farglitazar to the skin which is greater than A and less than B where A and B are as follows:
- a further embodiment of the invention consists in varying the dose regimen of farglitazar or a pharmaceutically acceptable salt thereof delivered to the skin.
- PPAR gamma agonists deliver their full pharmacological potential over a relatively long treatment period that normally ranges from 4 to 18 weeks (J.J. Nolan et al,
- 'Rosiglitazone taken once daily provides effective glycaemic control in patients with Type II diabetes mellitus', Diabetic Medicine (2000) 17, 287-294 ;
- P.Raskin et al, 'Rosiglitazone short-term monotherapy lowers fasting and post-prandial glucose in patients with Type II diabetes', Diabetologia (2000) 43, 278-284 ;
- L.S. Phillips el al,'Once- and twice-daily dosing with rosiglitazone improves glycemic control in patients with Type II diabetes', Diabetes Care (2001) 24(2), 308-315 ;
- Raskin et al. 'A randomized trial of rosiglitazone therapy in patients with inadequately controlled insulin-treated Type II diabetes', Diabetes Care (2001) 24(7), 1226-1232).
- the pharmacological benefit delivered is dose dependant.
- the rate at which this pharmacological benefit is delivered is also dose dependant.
- the clinical data generated by Raskin et al (2000) [P.Raskin et al, 'Rosiglitazone short-term monotherapy lowers fasting and post-prandial glucose in patients with type II diabetes', Diabetologia (2000) 43, 278-284] show that it takes about 8 weeks for a 2mg b.i.d.
- rosiglitazone dosage regimen to achieve a reduction of fasting plasma glucose by 2mmol/l, whilst it takes about 4 weeks for a 4mg b.i.d. rosiglitazone dosage regimen to achieve the same results.
- Similar observations on the dose regimen compared with time to achieve equivalent benefit can be made in other studies (J.J. Nolan et al, 'Rosiglitazone taken once daily porvides effective glycaemic control in patients with Type II diabetes mellitus', Diabetic Medicine (2000) 17, 287-294 ; L.S.
- Phillips et al.'Once- and twice-daily dosing with rosiglitazone improves glycemic control in patients with Type II diabetes', Diabetes Care (2001) 24(2), 308-315 ; P. Raskin et al., 'A randomized trial of rosiglitazone therapy in patients with inadequately controlled insulin-treated type 2 diabetes', Diabetes Care, (2001) 24(7), 1226-1232).
- increasing the dose to reduce this time to get a defined pharmacological response can lead to unwanted side effects, for example an unwanted systemic pharmacological effect such as an anti-hyperglycaemic effect.
- PPAR gamma agonists can be administered in the following ways.
- the treatment can be divided into two parts.
- the first part of the treatment consists of delivering a high topical dose for a short time ranging from one day to 12 weeks, preferably ranging from one day to 2 weeks.
- the second part of the treatment consists of delivering a lower dose, either topically or orally for the remaining part of the treatment. If for the second part of the treatment, the drug is delivered orally, it is preferred not to exceed the established orally safe dosage regimen.
- a method for treating a skin condition selected from the list consisting of psoriasis, atopic dermatitis, facial acne, rosacea, photoageing of the face, photoageing of the hands and skin cancer which comprises administering topically to the skin of a patient in need of treatment a first pharmaceutical composition for a first period of time and a second pharmaceutical composition for a second period of time, each pharmaceutical formulation containing a drug substance which is farglitazar or a pharmaceutically acceptable salt thereof characterised in that the first formulation delivers to the skin a nominal flux of said drug substance which is greater than the minimum nominal flux required to cause a therapeutic effect against the skin condition (hereinafter “lower limit nominal flux”) and less than the minimum nominal flux which will cause a systemic anti-hyperglycaemic effect (hereinafter “upper limit nominal flux”) and the second formulation delivers a nominal flux of said drug substance to the skin which is greater than the lower limit nominal flux but is less than the nominal flux delivered for the first
- the values of the "lower limit nominal flux" and the "upper limit nominal flux” may be
- a method for treating a skin condition selected from the list consisting of psoriasis, atopic dermatitis, facial acne, rosacea, photoageing of the face, photoageing of the hands and skin cancer which comprises administering topically to the skin of a patient in need of treatment a first pharmaceutical composition for a first period of time and a second pharmaceutical composition for a second period of time, each pharmaceutical formulation containing a drug substance which is farglitazar or a pharmaceutically acceptable salt thereof, characterised in that the first formulation delivers a nominal flux of said drug substance to the skin which is greater than A and less than B, wherein A and B are as defined above, and the second formulation delivers a nominal flux of said drug substance to the skin which is greater than A as defined above but is less than the nominal flux delivered for the first period of time.
- the first composition has a higher flux than the second composition in order to accelerate onset of therapeutic activity.
- the second composition of lower flux is intended to be suitable for maintenance therapy.
- the first period of time is a period of time long enough to establish onset of therapeutic activity, more particularly is long enough to establish at least 75% of maintenance level therapeutic activity.
- the first period of time will be between 1 day and 12 weeks, preferably 1 day to 2 weeks.
- the second period of time is the remainder of the treatment period.
- the second formulation delivers a nominal flux of drug substance to the skin which is greater than A as defined above but is less than the half the nominal flux delivered for the first period of time, more preferably less than one quarter nominal flux delivered for the first period of lime.
- a method for treating a skin condition selected from the list consisting of psoriasis, atopic dermatitis, facial acne, rosacea, photoageing of the face, photoageing of the hands and skin cancer which comprises administering topically to the skin of a patient in need of treatment for a first period of time a pharmaceutical composition containing a drug substance which is farglitazar or a pharmaceutically acceptable salt thereof characterised in that the formulation delivers to the skin a nominal flux of said drug substance which is greater than the minimum nominal flux required to cause a therapeutic effect against the skin condition (hereinafter “lower limit nominal flux”) and less than the minimum nominal flux which will cause a systemic anti-hyperglycaemic effect (hereinafter “upper limit nominal flux”) and subsequently administering the drug substance in an oral dosage form for a second period of time.
- a pharmaceutical composition containing a drug substance which is farglitazar or a pharmaceutically acceptable salt thereof characterised in that the formulation delivers to the skin a nominal flux of said drug substance which
- a skin condition selected from the list consisting of psoriasis, atopic dermatitis, facial acne, rosacea, photoageing of the face, photoageing of the hands, and skin cancer characterised in that the composition delivers to the skin for a first period of time a nominal flux of said drug substance which is
- compositions containing a drug substance which is farglitazar or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the topical treatment to the skin of a patient suffering from a skin condition selected from the list consisting of psoriasis, atopic dermatitis, facial acne, rosacea, photoageing of the face, photoageing of the hands, and skin cancer characterised in that the composition delivers to the skin for a first period of time a nominal flux of said drug substance which is greater than the minimum nominal flux required to cause a therapeutic effect against the skin condition and less than the minimum nominal flux which will cause a systemic anti- hyperglycaemic effect and said treatment is followed by administering said drug substance in an oral dosage form.
- the topical composition has a relatively high flux in order to accelerate onset of therapeutic activity.
- the oral dosage form is intended to be suitable for maintenance therapy.
- the first period of time is a period of time long enough to establish onset of therapeutic activity, more particularly is long enough to establish at least 75% of maintenance level therapeutic activity.
- the first period of time will be between 1 day and 12 weeks, preferably 1 day to 2 weeks.
- the second period of time is the remainder of the treatment period.
- the oral dosage composition may be effective in causing a systemic anti-hyperglycaemic effect in patients sensitive to systemic PPAR gamma agonist therapy (eg patients suffering from Type II diabetes mellitus or who would otherwise benefit from insulin sensitivity enhancement).
- the oral dosage form of farglitazar delivers 1.25 to 5mg per day.
- formulations adapted for topical administration to the skin capable of delivering fluxes according to the methods described above.
- Suitable formulations include ointments and solidified water/oil emulsion variants thereof, pastes, water/oil creams or lotions, oil/water creams or lotions, gels and rigid foams.
- Ointments are hydrocarbon-based semisolid formulations containing dissolved or suspended drugs. They can, for example be prepared by incorporating high melting waxes into mineral oil (liquid petrolatum). Due to problems of drug solubility, and inconvenience associated with their greasy nature, it is often more convenient to incorporate an aqueous medium into the hydrophobic base to yield an emulsion. Examples of such aqueous mediums are the use of propylene glycol or Polyoxyethylene polymers (polyetheylene glycol). Pastes are ointments into which a high percentage of insoluble paniculate solids have been incorporated.
- Creams and lotions are semi-solid emulsion systems and the term is applied both to water/oil or oil/water.
- the oil phase of an emulsion may comprise from 5-95% preferably from 5 to 40% of the composition by weight.
- Gel formulations are semi-solid systems in which a liquid phase is trapped in a polymeric matrix of a natural or synthetic gum.
- Rigid foams are systems in which air or some other gas is emulsified in a liquid phase to the point of stiffening.
- composition contains an oily phase
- excipients of this phase may comprise an oil based on animal, vegetable, mineral, silicone, fluorinated and/or synthetic oil.
- hydrocarbon oils such as; isohexadecane, paraffin oil or liquid petroleum jelly, petrolatum, microcrystalline wax, beeswax; perhydrosqualene, arara oil, sweet almond, calophyllum, palm, castor, avocado, jojoba, olive or cereal germ oil; alcohols such as oleyl alcohol, linoleyl or linolenyl alcohol, isostearyl alcohol, lanolin alcohol or octyl dodecanol.
- hydrocarbon oils such as; isohexadecane, paraffin oil or liquid petroleum jelly, petrolatum, microcrystalline wax, beeswax; perhydrosqualene, arara oil, sweet almond, calophyllum, palm, castor, avocado, jojoba, olive or cereal germ oil; alcohols such as oleyl alcohol, linoleyl or linolenyl alcohol, isostearyl alcohol, lanolin alcohol or octyl
- silicone oils such as dimethicones, dimethiconols, cyclomethicones, silicone waxes like alkyl dimethicones or stearoxytrimethylsilane, cross-linked silicone elastomers as well as other polydimethylsiloxanes derivatives, optionally phenylated, such as phenyltrimethicones.
- mono-, di- and triglycerides and their derivatives like caprylic/capric triglycerides.
- esters such as methyl myristate, ethyl myristate, isopropyl myristate, butyl myristate, isobutyl myristate, methyl palmitate, ethyl palmitate, isopropyl palmitate, octyl palmitate, 2-ethylhexyl palmitate, cetyl palmitate, C12-15 alkyl benzoate, ethyl oleate, decyl oleate, butyl stearate, isopropyl isostearate, dioctyl adipate, diisopropyl adipate, 2-ethylhexyl hexanoate, 2-ethylhexyl 2-ethylhexanoate, ethyl laurate, isohexyl laurate, hexyl laurate, octyldodecyl octanoate,
- compositions according to the invention may comprise, in addition:
- An emulsification agent for dispersing the oil phase for example an anionic surfactant like carboxylic acids, carboxylic acids esters, sulfuric acid esters, sulfonic acids, amino acid amides; a cationic surfactant like polyoxyethylene alkyl amines, tetraalkyl ammonium salts; an amphoteric surfactant like phospholipids, N-alkyl amino acids, alkylamido alkylamines; a nonionic surfactants like fatty alcohols, alkoxylated fatty alcohols, polyoxyethylene-phenol esters, alkoxylated fatty acids, acyl sorbitans, polyoxyethylene-derivatives, acyl glycerides, polyoxyethylene alkyl amides, polyoxyethylene/polyoxypropylene block copolymers, polyoxyethylene silicone derivatives, alkylmethyl siloxane copolyol, alkyl-substituted polyvinyl polymers.
- emulsifying systems well known to the art and comprising of glyceryl stearate, glyceryl distearate, glyceryl oleate, propylene glycol stearate, glycol sferate, glyceryl stearafe/PEG 100 stearate, sorbitan sesquioleate, cetyl alcohol, stearyl alcohol, sodium lauryl sulfate and cetomacrogol.
- An agent affecting the suspension of the oil phase for example a copolymer of C.sub.10 -C.sub.30 alkyl acrylates and acrylic or methacrylic acid or ester thereof; or an acrylamide/methylpropane-sulfonic acid copolymer.
- An agent for modifying its viscosity, and to provide textures which are gelled to a greater or lesser degree such as: cellulose derivatives (carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose); natural gums such as xanthan, guar and carob gums, scleroglucans, chitin or chitosan derivatives, carrageenans; polycarboxyvinyl derivatives of the Carbomer type.
- compositions according to the invention may also comprise conventional additives and adjuvants for dermatological applications, such as preservatives, especially paraben esters like methylparaben, ethylparaben, propylparaben, butylparaben, or quaternary ammonium compounds like benzalkonium chloride, or formaldehyde donors like imidazonidinyl urea, or alcohols like benzyl alcohol, phenoxyethanol or acids like benzoic acid, sorbic acid ; acids or bases used as pH buffer excipients; antioxidants, especially phenolic antioxidants like hydroquinone, tocopherol and derivatives thereof, as well as flavonoids, or miscellaneous antioxidants like ascorbic acid, ascorbyl palmitate; perfumes; fillers such as kaolin or starch; pigments or colorants; UV- screening agents; moisturizers, especially glycerin, butylene glycol, hexylene glycol, urea, hyaluronic
- Polyethylene glycol 4000 (Carbowax 4000) 50% (w/w), polyethylene glycol 400 50%
- Oil phase spermaceti 12.5% (w/w), white wax 12.0%, almond oil 55.58%
- Aqueous phase sodium borate 0.5% (w/w), purified water 19%
- Oil phase stearic acid 13% (w/w), stearyl alcohol 1%, cetyl alcohol 1%
- Aqueous phase glycerine 10% (w/w), methylparaben 0.025%, propylparaben 0.015%, potassium hydroxide 0.9%, purified water qs to 100%
- Oil phase stearic alcohol 15% (w/w), beeswax 8%, sorbitan monooleate 1.25%
- Aqueous phase 70% sorbitol solution 7.5% (w/w), polysorbate 80 3.75%, methylparaben 0.025%, propylparaben 0.015%, purified water qs to 100%
- Methocel 90 HC 4000 0.8% (w/w), Carbopol 934 0.24%, propylene glycol 16.7%, methylparaben 0.015%, sodium hydroxide qs to pH 7, purified water qs to 100% 0 Further details concerning suitable formulations may be obtained by reference to standard textbooks eg Modern Pharmaceutics (2002) vol 121 Published Marcel Dekker, Ed Banker and Rhodes or Harry's cosmeticology (2000), 8 th Edition, Chemical Publishing Co, Ed Gordon R.
- drug substances for 5 oral administration may, for example, be in solid oral dosage forms or liquid oral dosage forms.
- Example solid oral dosage forms include tablet or capsule form and may as necessary contain conventional excipients such as binding agents, fillers, lubricants, glidants, disintegrants and wetting agents. Unit dose compositions are preferred.
- binding agents include acacia, alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, dextrates, dextrin, dextrose, ethylcellulose, gelatin, liquid glucose, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium aluminium silicate, maltodextrin, methyl cellulose, polymethacrylates, polyvinylpyrrolidone, 5 pregelatinised starch, sodium alginate, sorbitol, starch, syrup, tragacanth.
- fillers include calcium carbonate, calcium phosphate, calcium sulphate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, compressible sugar, confectioner's sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, dibasic calcium phosphate, fructose, glyceryl palmitostearate, 0 glycine, hydrogenated vegetable oil-type 1 , kaolin, lactose, maize starch, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, microcrystalline cellulose, polymethacrylates, potassium chloride, powdered cellulose, pregelatinised starch, sodium chloride, sorbitol, starch, sucrose, sugar spheres, talc, tribasic calcium phosphate, xylitol.
- lubricants include calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, microcrystalline cellulose, sodium benzoate, sodium chloride, sodium lauryl sulphate, stearic acid, sodium stearyl fumarate, talc, zinc stearate.
- glidants include colloidal silicon dioxide, powdered cellulose, magnesium trisilicate, silicon dioxide, talc.
- disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminium silicate, microcrystalline cellulose, methyl cellulose, polyvinylpyrrolidone, polacrilin potassium, pregelatinised starch, sodium alginate, sodium lauryl sulphate, sodium starch glycollate.
- An example of a pharmaceutically acceptable wetting agent is sodium lauryl sulphate.
- the solid oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are of course conventional in the art.
- the tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.
- Oral liquid preparations may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
- Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents.
- suspending agents for example sorbitol, syrup, methyl cellulose,
- the nominal flux delivered by a given topical composition may be determined in vivo or in vitro.
- the in vivo method which employs healthy human volunteers is as follows:
- the test composition is applied to the back of an individual at around 2 mg of formulation per cm 2 .
- the area of the site treated must be measured.
- the site treated must be left opened for 2 hours prior to the individual wearing a cotton T-shirt for the remainder of the study.
- Plasma concentration measurements are made every 4 hours over a 24 hours period.
- the flux is calculated from the plasma level achieved using classical pharmacokinetics as described by Hadgraft et al ('Investigations on the percutaneous absorption of the antidepressant rolipram in vitro and in vivo'-Hadgraft et al (1990) Pharm. Res. 7, 1307-1312).
- Flux (ng/cm 2 /hr) Mean total plasma concentration over 24 hours (ng/ml) * total systemic clearance (ml/hr)/surface area (cm 2 )
- the alternative in vitro method involves an in vitro percutaneous study. The method which essentially follows Colipa recommendations (European Commission - 99/III/COS/87 - Basic Criteria for the in
- SCCNFP/0167/99/Final - 23rd June 1999 requires the use of opened diffusion cells (flow-through type, eg Permegear brand) that are temperature controlled to 32 °C (to mimic skin temperature) and which allow application of a thin film with an upper donor chamber and a lower receptor chamber.
- the diffusion cells should be sufficiently
- a clinically relevant dose is considered to be around 2mg of the formulation per cm 2 for the skin condition treated. If higher doses were to be applied, experiments proving linearity towards a clinical dose would be required.
- the human skin used should be dermatomed to approximately 300-500 ⁇ m and sourced from the back of
- Skin batch integrity should be assessed with the use of a controlled solution of known flux (e.g. caffeine, methyl paraben).
- Drug follows through to a receptor mimicking well physiological condition and which does not contain solvents or other materials that would in luence the integrity of the skin barrier.
- the preferred receptor is aqueous Phosphate Buffer Salined receptor. Study lime is equal to about
- the flux is determined by the in vivo measurement, although that it would be expected that the in vitro system is a satisfactory model for the in vivo system.
- the skin condition of particular interest is psoriasis.
- compositions for use in the aforementioned methods and uses which comprise farglitazar or a pharmaceutically acceptable salt thereof and a physiologically acceptable carrier.
- the carrier will be physiologically acceptable on topical administration.
- a pharmaceutical composition comprising a drug substance which is farglitazar or a pharmaceutically acceptable salt thereof and a physiologically acceptable carrier characterised in that the formulation delivers to the skin a nominal flux of said drug substance which is greater than a lower limit nominal flux defined as the minimum nominal flux required to cause a therapeutic effect against the skin condition and less than an upper limit nominal flux defined as the minimum nominal flux which will cause a systemic anti- hyperglycaemic effect.
- the PPAR gamma agonist may be employed in combination with another therapeutic substance of benefit in topical administration, for example a corticosteroid (eg fluticasone propionate or mometasone furoate), a vitamin D3 derivative (eg calcipotriol), a retinoid (eg relinol,tazarolene, or trans- or cis-retinoic acid) or an immunomodulator (eg pimecrolimus or tacrolimus).
- a corticosteroid eg fluticasone propionate or mometasone furoate
- a vitamin D3 derivative eg calcipotriol
- a retinoid eg relinol,tazarolene, or trans- or cis-retinoic acid
- an immunomodulator eg pimecrolimus or tacrolimus
- treatment embraces treatment of established conditions as well as prophylaxis if appropriate
- Farglitazar is preferably employed as the free acid or the sodium salt.
- all weights and amounts of farglitazar are based on the weight or amount of free acid, and when farglitazar is employed as a salt a correspondingly larger amount (to take account of the weight or amount of the salt) will be employed. Examples
- Figure 1 Structure of mammalian skin Throughout the specification and the claims which follow, unless the context requires otherwise, the word 'comprise', and variations such as 'comprises' and 'comprising', will be understood to imply the inclusion of a stated integer or step or ⁇ group of integers but not to the exclusion of any other integer or step or group of integers or steps. Above mentioned patents and patent applications are hereinbefore incorporated by reference.
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Abstract
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FR2897534A1 (en) * | 2006-02-17 | 2007-08-24 | Galderma Res & Dev | USE OF TESAGLITAZAR FOR THE PREPARATION OF A PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF DERMATOLOGICAL DISEASES |
CA2710333A1 (en) * | 2008-01-03 | 2009-07-09 | Abbott Biotechnology Ltd. | Predicting long-term efficacy of a compound in the treatment of psoriasis |
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AU2001288271A1 (en) * | 2000-08-17 | 2002-02-25 | Harrihar A. Pershadsingh | Methods for treating inflammatory diseases |
US6573287B2 (en) * | 2001-04-12 | 2003-06-03 | Bristo-Myers Squibb Company | 2,1-oxazoline and 1,2-pyrazoline-based inhibitors of dipeptidyl peptidase IV and method |
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