NZ618546B2 - Pharmaceutical composition, methods for treating and uses thereof - Google Patents
Pharmaceutical composition, methods for treating and uses thereof Download PDFInfo
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- NZ618546B2 NZ618546B2 NZ618546A NZ61854612A NZ618546B2 NZ 618546 B2 NZ618546 B2 NZ 618546B2 NZ 618546 A NZ618546 A NZ 618546A NZ 61854612 A NZ61854612 A NZ 61854612A NZ 618546 B2 NZ618546 B2 NZ 618546B2
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- renal
- obesity
- diabetes
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- MSXHSNHNTORCAW-UHFFFAOYSA-M sodium 3,4,5,6-tetrahydroxyoxane-2-carboxylate Chemical compound [Na+].OC1OC(C([O-])=O)C(O)C(O)C1O MSXHSNHNTORCAW-UHFFFAOYSA-M 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
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- 239000007901 soft capsule Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 230000000087 stabilizing Effects 0.000 description 1
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- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical compound OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 1
- 239000002600 sunflower oil Substances 0.000 description 1
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- 238000002076 thermal analysis method Methods 0.000 description 1
- 229960005371 tolbutamide Drugs 0.000 description 1
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- 238000002054 transplantation Methods 0.000 description 1
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- 239000003981 vehicle Substances 0.000 description 1
- 229960001254 vildagliptin Drugs 0.000 description 1
- XTXRWKRVRITETP-UHFFFAOYSA-N vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 1
- 229960001729 voglibose Drugs 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
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- 239000000811 xylitol Substances 0.000 description 1
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- 239000005019 zein Substances 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- WHGYBXFWUBPSRW-FOUAGVGXSA-N β-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 1
Classifications
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- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Abstract
Disclosed herein is the use of the SGLT-2 inhibitor 1-chloro-4-(B-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene in the manufacture of a medicament for the treatment or prevention of renal hyperfiltrative injury wherein the patient has a glomerular filtration rate (GFR) equal to or greater than 140mL/min/1.73 m2, wherein the medicament comprises 10 mg or 25 mg of the SGLT2 inhibitor, and wherein the patient is an individual diagnosed or showing one or more of the following conditions: (a) diabetes mellitus; (b) congenital or acquired obstructive uro/nephropathy; (c) progressive chronic kidney disease (CKD); (d) acute renal failure (ARF); (e) renal transplant recipients; (f) renal transplant donors; or (g) unilateral total or partial nephrectomized patients. The medicament is often useful in patients diagnosed with metabolic disorders and related conditions, in particular diabetes mellitus and kidney disfunction. l to or greater than 140mL/min/1.73 m2, wherein the medicament comprises 10 mg or 25 mg of the SGLT2 inhibitor, and wherein the patient is an individual diagnosed or showing one or more of the following conditions: (a) diabetes mellitus; (b) congenital or acquired obstructive uro/nephropathy; (c) progressive chronic kidney disease (CKD); (d) acute renal failure (ARF); (e) renal transplant recipients; (f) renal transplant donors; or (g) unilateral total or partial nephrectomized patients. The medicament is often useful in patients diagnosed with metabolic disorders and related conditions, in particular diabetes mellitus and kidney disfunction.
Description
PHARMACEUTICAL COMPOSITION, METHODS FOR TREATING AND
USES THEREOF
Technical Field of the Invention
The invention relates to the treatment or prevention of renal impairment and/or complications,
such as nephropathy, using a SGLT-2 tor, for example in patients diagnosed with
metabolic disorders and related ions.
Background of the Invention
Kidneys are bean-shaped organs, located near the middle of the back. Inside each kidney about a
million tiny structures called nephrons filter blood. They remove waste products and extra
water, which become urine. Damage to the nephrons represents one form of kidney disease. This
damage may leave kidneys unable to remove wastes. Some damage, e.g. damage related to
hyperfiltration can occur slowly over years, initially often without obvious symptoms.
The ‘hyperfiltrative hypothesis’ implies that the excess demand on a limited renal reserve
produces adaptive and ultimately pathologic changes in the kidney which finally lead to
‘nephron tion’. At the single-nephron level, hyperfiltration is hypothesized to be an early
link in the chain of events that lead from intraglomerular hypertension to nuria and,
subsequently, to reduced Glomerular tion Rate (GFR). Based on this hypothesis such a
finding therefore ents a risk for subsequent renal injury and could be classified as an early
manifestation of renal damage often referred to as the hyperfiltrative stage. Such renal
hyperfiltration can lead to early glomerular s and to microalbuminuria, which itself can
lead to macroalbuminuria and to age renal disease.
The influence of hyperfiltration on renal function e has been most thoroughly evaluated in
kidney transplant recipients and donors, and in patients uninephrectomized for acquired renal
disease, but also in patients with es mellitus (Magee et al. Diabetologia 2009; 52: 691–
697). In theory, any reduction in functional nephron number will lead to adaptive glomerular
hypertension and hyperfiltration r induced genetically, surgically, or by acquired renal
disease. Moreover, hyperfiltration has been shown to occur in certain pathophysiologic
conditions even when renal mass is intact, e.g. in diabetes.
AH26(10398701_1):RTK
Therefore, there is a medical need for methods, ments and pharmaceutical compositions
with a good efficacy with regard to renal hyperfiltrative injury.
Summary of the Invention
According to a first aspect, the t invention provides use of the SGLT2 inhibitor 1-chloro-
4-(β-D-glucopyranosyl)[4-((S)-tetrahydrofuranyloxy)-benzyl]-benzene for the
manufacture of a medicament for preventing, slowing the ssion of, delaying or treating
renal hyperfiltrative injury in a patient in need thereof, wherein the patient has a glomerular
filtration rate (GFR) equal to or greater than 140mL/min/1.73 m2, wherein the medicament
comprises 10 mg or 25 mg of the SGLT2 inhibitor, and wherein the patient is an individual
diagnosed or showing one or more of the ing conditions:
(a) es mellitus;
(b) congenital or ed obstructive uro/nephropathy;
(c) progressive chronic kidney disease (CKD);
(d) acute renal failure (ARF);
(e) renal transplant recipients;
(f) renal lant donors; or
(g) unilateral total or partial nephrectomized ts.
According to a second aspect, the present invention provides use of the SGLT2 inhibitor 1-
chloro(β-D-glucopyranosyl)[4-((S)-tetrahydrofuranyloxy)-benzyl]-benzene for the
manufacture of a medicament for preventing, slowing the progression of, delaying or treating a
condition or disorder selected from the group consisting of hyperfiltrative diabetic nephropathy,
renal hyperfiltration, glomerular hyperfiltration, renal aft hyperfiltration, compensatory
hyperfiltration, hyperfiltrative chronic kidney disease, hyperfiltrative acute renal failure and
compensatory hyperfiltration, wherein the compensatory hyperfiltration is in association with
obstructive uro/nephropathy or morbid obesity, in a patient in need thereof, wherein the t
has a GFR equal to or greater than 140 /1.73 m2, n the medicament comprises 10
mg or 25 mg of the SGLT2 inhibitor, and wherein the patient is an individual diagnosed or
showing one or more of the following conditions:
(a) diabetes mellitus;
(b) ital or acquired obstructive uro/nephropathy;
(c) progressive chronic kidney disease (CKD)
AH26(10877199_1):JJC
(d) acute renal failure (ARF);
(e) renal lant recipients;
(f) renal transplant donors; or
(g) unilateral total or partial nephrectomized patients.
The present invention provides methods for preventing, slowing the progression of, delaying or
treating renal hyperfiltrative injury in a patient in need thereof characterized in that a
pharmaceutical composition comprising an SGLT2 inhibitor is stered to the patient,
AH26(10398701_1):RTK
n the SGLT2 inhibitor is 1-chloro(B-D-glucopyranosy|)[4-((S)—tetrahydrofuran-
3-yloxy)—benzyl]—benzene or a prodrug thereof. In one aspect, the patient is an individual
diagnosed or showing one or more of the following conditions:
(a) diabetes mellitus;
(b ) ital or acquired obstructive uro/nephropathy;
(c) progressive chronic kidney disease (CKD);
(d) acute renal e (ARF);
(e) renal transplant recipients;
(f) renal transplant donors; or
(g) unilateral total or partial nephrectomized patients.
In ular, in one aspect, the patient is an individual diagnosed with or g diabetes
mellitus. In a further aspect, the patient is an individual sed with or showing type 1
diabetes mellitus or type 2 diabetes mellitus. In a further aspect, the t is an individual
diagnosed with or showing other types of diabetes mellitus, such as e.g. maturity onset
diabetes of the youth (MODY) or latent autoimmune diabetes of adults (LADA). In a r
aspect, the patient is an individual diagnosed with or showing pre-diabetes.
In one aspect, the patient has an GFR equal to or greater than 125 mL/min/1.73 m2. In a
further aspect, the patient has an GFR equal to or r than 140 mL/min/1.73 m2.
In one aspect, the patient:
(1) is an individual diagnosed of one or more of the conditions selected from the group
consisting of ovenNeight, y, visceral obesity and abdominal obesity; or
(2) is an dual who shows one, two or more of the following conditions:
(a) a fasting blood glucose or serum glucose concentration greater than 100
mg/dL, in particular greater than 125 mg/dL;
(b) a postprandial plasma glucose equal to or greaterthan 140 mg/dL;
(c) an HbA1c value equal to or greater than 6.0 %, in particular equal to or
greater than 6.5%, in particular equal to or greaterthan 8.0 %; or
(3) is an individual wherein one, two, three or more of the following conditions are
present:
(a) obesity, visceral obesity and/or abdominal obesity,
(b) triglyceride blood level 2 150 mg/dL,
(c) HDL-cholesterol blood level < 40 mg/dL in female patients and < 50 mg/dL in
male patients,
(d) a systolic blood pressure 2 130 mm Hg and a lic blood pressure 2 85
mm Hg,
(e) a fasting blood glucose level 2 100 mg/dL; or
(4) is an individual with morbid obesity.
In one aspect, the pharmaceutical composition additionally comprises one or more
pharmaceutically acceptable carriers. In one aspect, the pharmaceutical composition
comprises the SGLT-2 inhibitor in a range from about 10 mg to 25 mg. In one aspect, the
pharmaceutical composition comprises 10 mg or 25 mg of the SGLT-2 inhibitor.
In a further embodiment, the present invention es methods for preventing, g the
progression of, delaying or treating a condition or disorder selected from the group consisting
of iltrative diabetic nephropathy, renal hyperfiltration, glomerular hyperfiltration, renal
allograft hyperfiltration, compensatory iltration (e.g. after renal mass reduction by
surgery), hyperfiltrative c kidney disease, hyperfiltrative acute renal failure,
compensatory hyperfiltration in association with obstructive uro/nephropathy and morbid
obesity in a patient in need thereof characterized in that a ceutical composition
comprising an SGLT2 tor is administered to the patient, wherein the SGLT2 inhibitor is
ro(B-D-glucopyranosyl)[4-((S)—tetrahydrofuranyloxy)—benzyl]—benzene or a
prodrug f. In one aspect, the patient is an individual diagnosed or showing one or more
of the following conditions:
(a) diabetes us;
(b ) congenital or acquired obstructive uro/nephropathy;
(c) progressive c kidney e (CKD);
(d) acute renal failure (ARF);
(e) renal transplant recipients;
(f) renal transplant donors; or
(g) unilateral total or partial nephrectomized patients.
In particular, in one aspect, the patient is an individual diagnosed with or showing diabetes
mellitus. In a further aspect, the t is an individual sed with or showing type 1
diabetes mellitus or type 2 diabetes mellitus. In a further aspect, the patient is an individual
diagnosed with or showing other types of es mellitus, such as e.g. maturity onset
diabetes of the youth (MODY) or latent autoimmune diabetes of adults (LADA). In a further
aspect, the patient is an individual diagnosed with or showing pre-diabetes.
In one aspect, the patient has an GFR equal to or greater than 125 mL/min/1.73 m2. In a
further aspect, the patient has an GFR equal to or greater than 140 mL/min/1.73 m2.
In one aspect, the patient:
WO 07557
(1) is an individual diagnosed of one or more of the conditions selected from the group
consisting of ovenNeight, obesity, visceral obesity and nal obesity; or
(2) is an individual who shows one, two or more of the following conditions:
(a) a fasting blood glucose or serum glucose tration greater than 100
mg/dL, in particular greater than 125 mg/dL;
(b) a postprandial plasma glucose equal to or greaterthan 140 mg/dL;
(c) an HbA1c value equal to or greater than 6.0 %, in particular equal to or
greater than 6.5%, in particular equal to or greaterthan 8.0 %;
(3) is an individual wherein one, two, three or more of the following conditions are
t:
(a) obesity, visceral y and/or abdominal obesity,
(b) triglyceride blood level 2 150 mg/dL,
(c) HDL-cholesterol blood level < 40 mg/dL in female patients and < 50 mg/dL in
male patients,
(d) a systolic blood pressure 2 130 mm Hg and a diastolic blood pressure 2 85
mm Hg,
(e) a fasting blood glucose level 2 100 mg/dL; or
(4) is an individual with morbid obesity.
In one aspect, the pharmaceutical composition additionally comprises one or more
pharmaceutically acceptable carriers. In one aspect, the pharmaceutical ition
comprises the SGLT-2 inhibitor in a range from about 10 mg to 25 mg. In one aspect, the
pharmaceutical composition comprises 10 mg or 25 mg of the SGLT-2 inhibitor.
In addition, the present invention relates to the SGLT-2 inhibitor bed herein for use in a
method as described hereinbefore and hereinafter, and to the use of the SGLT2 tor for
the manufacture of a medicament for use in a method as described hereinbefore and
hereinafter.
The invention also relates to a pharmaceutical composition according to this invention for use
in a method as described hereinbefore and hereinafter, and to the use of a pharmaceutical
ition according to this invention for the manufacture of a medicament for use in a
method as described hereinbefore and hereinafter.
In ular, in one aspect, the present invention provides a SGLT-2 inhibitor or a
ceutical composition described herein for use in preventing, slowing the progression
of, ng or treating renal hyperfiltrative injury. In a further aspect, the present invention
provides a SGLT-2 inhibitor or a pharmaceutical composition described herein for use in
preventing, slowing the progression of, delaying or treating a condition or disorder ed
from the group consisting of hyperfiltrative diabetic nephropathy, renal hyperfiltration,
glomerular hyperfiltration, renal allograft hyperfiltration, compensatory hyperfiltration (e.g.
after renal mass reduction by y), hyperfiltrative chronic kidney disease, hyperfiltrative
acute renal failure, compensatory hyperfiltration in association with obstructive
uro/nephropathy and morbid obesity.
In a r aspect, the present invention provides the use of a SGLT-2 inhibitor or a
pharmaceutical composition described herein for preventing, slowing the progression of,
ng or treating renal hyperfiltrative injury. In a r aspect, the present invention
provides the use of a SGLT-2 inhibitor or a pharmaceutical composition described herein for
preventing, slowing the progression of, delaying or ng a condition or disorder selected
from the group consisting of hyperfiltrative diabetic pathy, renal hyperfiltration,
glomerular hyperfiltration, renal allograft hyperfiltration, compensatory hyperfiltration (e.g.
after renal mass reduction by surgery), iltrative chronic kidney disease, hyperfiltrative
acute renal failure, compensatory hyperfiltration in association with obstructive
uro/nephropathy and morbid obesity.
Definitions
The term "active ingredient" of a pharmaceutical composition according to the present
invention means the SGLT2 inhibitor according to the present invention. An “active
ingredient is also sometimes referred to herein as an “active substance”.
The term “hyperfiltration” is d as an elevation in the filtration rate of the renal
glomeruli. In one aspect, hyperfiltration is defined as a whole kidney filtration rate equal to or
greater than 125 mL/min/1.73 m2, especially equal to or greater than 140 mL/min/1.73 m2, as
measured using a method described below. Hyperfiltration may also be d as
d to an absolute GFR greater to the 90‘“, or the 95‘“, percentile in the studied population
after adjusting for sex, age, weight, height, and the use of ACE inhibitors or ARB (see
Melsom et al. Diabetes Care 2011; DOI: 10.2337/dc11-0235).
The term “glomerular tion rate (GFR)” is defined as the volume of fluid filtered from
the renal (kidney) glomerular capillaries into the Bowman's capsule per unit time. It is
indicative of overall kidney function. The glomerular filtration rate (GFR) can be ated by
ing any chemical that has a steady level in the blood, and is freely filtered but neither
reabsorbed nor secreted by the kidneys. The rate therefore measured is the quantity of the
substance in the urine that originated from a calculable volume of blood. The GFR is typically
recorded in units of volume per time, e.g., milliliters per minute and the formula below can be
used:
GFR = (Urine Concentration X Urine Volume)lPlasma Concentration
The GFR can be determined by injecting inulin into the plasma. Since inulin is neither
reabsorbed nor secreted by the kidney after glomerularfiltration, its rate of excretion is
directly proportional to the rate of filtration of water and solutes across the glomerular . A
normal value is: GFR = 90-125 /1.73 m2, in ular GFR = 100-125 mL/min/1.73
Other principles to determine GFR involve measuring 51 A, [125l]iothalamate or
iohexol.
The “estimated glomerular filtration rate (eGFR)” is defined as derived at screening from
serum creatinine values based on e.g., the Chronic Kidney Disease Epidemiology
Collaboration (CKD-EPI) equation, the Cockcroft-Gault formula or the Modification of Diet in
Renal Disease (MDRD) formula, which are all known in the art.
Subjects with normal renal function are defined as eGFR 290 ml/min. Subjects with mild
impairment of renal function as d eGFR 260 and <90 ml/min). ts with moderate
impairment as defined as eGFR 230 and <60 ml/min). Subjects with severe impairment as
defined as eGFR 215 and <30 ml/min.
The term “renal hyperfiltrative injury” is defined as a manifestation of renal damage
caused predominantly by renal hyperfiltration, which often is an early link in the chain of
events to further renal injury, acknowledging that hyperfiltration often works in concert with
other chronic kidney disease risk factors in the enesis of renal injury.
The term "body mass index" or "BMI" of a human t is defined as the weight in
ams divided by the square of the height in meters, such that BMI has units
of kg/m2.
The term "overweight" is defined as the condition wherein the adult individual of Europide
origin has a BMI greater than or 25 kg/m2 and less than 30 kg/m2. ln ts of Asian origin
the term “overweight” is defined as the condition wherein the adult individual has a BMI
greater than or 23 kg/m2 and less than 25 kg/m2. The terms "ovenNeight" and "pre-obese" are
used interchangeably.
The term "obesity" is defined as the ion wherein the adult individual of Europid origin
has a BMI equal to or greater than 30 kg/m2. According to a WHO definition the term obesity
may be categorized as follows: the term "class I obesity" is the condition wherein the BMI is
equal to or greater than 30 kg/m2 but lower than 35 kg/m2; the term "class II obesity" is the
condition wherein the BMI is equal to or greater than 35 kg/m2 but lower than 40 kg/m2; the
term "class III obesity" is the condition wherein the BMI is equal to or greater than 40 kg/m2.
|n subjects of Asian origin the term “obesity” is defined as the condition wherein the adult
dual has a BMI equal or greater than 25 kg/m2. Obesity in Asians may be categorized
further as follows: the term "class I obesity" is the condition wherein the BMI is equal to or
greater than 25 kg/m2 but lower than 30 kg/mz; the term "class II y" is the ion
wherein the BMI is equal to or greater than 30 kg/mz.
The term "visceral obesity" is defined as the condition n a waist-to-hip ratio of
r than or equal to 1.0 in men and 0.8 in women is measured. It defines the risk for
insulin resistance and the pment of pre-diabetes.
The term "abdominal obesity" is usually defined as the condition wherein the waist
circumference is > 40 inches or 102 cm in men, and is > 35 inches or 94 cm in women (for
normal ranges of popupations, see for example “Joint scientific statement (IDF, NHLBI, AHA,
WHO, IAS, IASO). Circulation 2009; 120:1640-1645“). With regard to a Japanese ethnicity or
Japanese patients abdominal y may be defined as waist circumference 2 85 cm in men
and 2 90 cm in women (see e.g. investigating committee for the diagnosis of metabolic
syndrome in Japan).
The term “morbid obesity” is defined herein as a condition in which the individual of
Europid origin has a BMI > 40 or has a BMI > 35 and a comorbidity such as diabetes melitus
or hypertension (see World Health Organization. Obesity: ting and ng the
Global Epidemic: Report on a WHO Consultation. World Health Organ Tech Rep Ser. 2000;
894: i—xii, 1—253).
The term “euglycemia” is defined as the condition in which a subject has a fasting blood
glucose concentration within the normal range, greater than 70 mg/dL (3.89
mmol/L) and less than 100 mg/dL (5.6 mmol/L), and a 2h postprandial glucose concentration
less than 140 mg/dl. The word “fasting” has the usual meaning as a medical term.
The term “hyperglycemia” is defined as the ion in which a subject has a fasting blood
glucose concentration above the normal range, greater than 100 mg/dL (5.6 mmol/L). The
word “fasting” has the usual meaning as a medical term.
The term “hypoglycemia” is defined as the condition in which a subject has a blood e
concentration below the normal range, in particular below 70 mg/dL (3.89
mmol/L).
The term "postprandial hyperglycemia" is defined as the condition in which a subject has
a 2 hour postprandial blood glucose or serum glucose concentration greater than 200 mg/dL
(11.11 mmol/L).
The term “impaired fasting blood glucose” or "IFG" is defined as the condition in which a
subject has a g blood glucose concentration or fasting serum glucose tration in a
range from 100 to 125 mg/dl (i.e. from 5.6 to 6.9 mmol/l. A subject with "normal fasting
glucose" has a fasting e concentration smaller than 100 mg/dl, i.e. smallerthan 5.6
mmol/l.
The term “impaired glucose tolerance” or "IGT" is defined as the condition in which a
subject has a 2 hour andial blood glucose or serum glucose concentration greater than
140 mg/dl (7.78 mmol/L) and less than 200 mg/dL (11.11 mmol/L). The abnormal glucose
tolerance, i.e. the 2 hour andial blood glucose or serum glucose concentration can be
measured as the blood sugar level in mg of glucose per dL of plasma 2 hours after taking 75
g of glucose after a fast. A subject with "normal glucose tolerance" has a 2 hour postprandial
blood glucose or serum glucose concentration smaller than 140 mg/dl (7.78 mmol/L).
The term insulinemia” is defined as the condition in which a subject with insulin
resistance, with or without euglycemia, has fasting or postprandial serum or plasma insulin
concentration elevated above that of normal, lean individuals without n resistance,
having a waist-to-hip ratio < 1.0 (for men) or < 0.8 (for .
The terms "insulin-sensitizing", in resistance-improving" or "insulin resistance-lowering”
are synonymous and used interchangeably.
The term “insulin resistance” is defined as a state in which circulating insulin levels in
excess of the normal response to a glucose load are ed to maintain the euglycemic
state (Ford ES, etal. JAMA. (2002) 287:356-9). A method of determining insulin resistance is
the euglycaemic-hyperinsulinaemic clamp test. The ratio of insulin to glucose is determined
within the scope of a combined insulin-glucose infusion technique. There is found to be
insulin resistance if the glucose absorption is below the 25th percentile of the background
population investigated (WHO tion). Rather less laborious than the clamp test are so
called l models in which, during an intravenous e tolerance test, the insulin and
glucose concentrations in the blood are measured at fixed time intervals and from these the
insulin resistance is calculated. With this method, it is not possible to distinguish between
hepatic and peripheral insulin resistance.
Furthermore, insulin resistance, the response of a patient with insulin resistance to therapy,
insulin sensitivity and hyperinsulinemia may be quantified by assessing the “homeostasis
model assessment to insulin resistance (HOMA-IR)” score, a reliable indicator of insulin
resistance (Katsuki A, et al. Diabetes Care 2001; 24: 362-5). Further reference is made to
methods for the determination of the HOMA—index for insulin sensitivity (Matthews et al.,
Diabeto/ogia 1985, 28: ), of the ratio of intact proinsulin to insulin (Forst et al.,
Diabetes 2003, 52(Suppl. 1): A459) and to an euglycemic clamp study. In addition, plasma
adiponectin levels can be monitored as a potential surrogate of insulin sensitivity. The
estimate of insulin resistance by the homeostasis assessment model (HOMA)—|R score is
calculated with the formula (Galvin P, et al. Diabet Med 1992;9:921-8):
HOMA-IR = [fasting serum insulin (uU/mL)] x [fasting plasma glucose(mmol/L)/22.5]
As a rule, other parameters are used in everyday clinical practice to assess insulin
resistance. Preferably, the t's ceride concentration is used, for example, as
increased triglyceride levels correlate icantly with the presence of insulin resistance.
Patients with a predisposition for the development of IGT or IFG or type 2 diabetes are those
having euglycemia with nsulinemia and are by definition, insulin resistant. A typical
patient with insulin ance is usually ovenNeight or obese. lf insulin resistance can be
detected, this is a particularly strong indication of the presence of pre-diabetes. Thus, it may
be that in order to maintain e homoeostasis a person needs 2-3 times as much n
as a healthy person, without this resulting in any clinical ms.
The methods to investigate the on of atic beta-cells are r to the above
methods with regard to insulin sensitivity, nsulinemia or insulin resistance: An
improvement of beta-cell function can be measured for example by determining a HOMA-
index for ell function (Matthews et al., Diabetologia 1985, 28: 412-19), the ratio of
intact ulin to insulin (Forst et al., Diabetes 2003, 52(Suppl. 1): A459), the insulin/C-
peptide ion after an oral glucose tolerance test or a meal tolerance test, or by
employing a hyperglycemic clamp study and/or minimal modeling after a frequently sampled
intravenous e tolerance test (Stumvo/I et a/., EurJ Clin Invest 2001, 31: 380-81).
The term “pre-diabetes” is the condition wherein an individual is pre-disposed to the
development of type 2 diabetes. Pre-diabetes extends the definition of impaired glucose
tolerance to include individuals with a g blood e within the high normal range 2
100 mg/dL (J. B. Meigs, etal. es 2003; 52:1475-1484) and g hyperinsulinemia
(elevated plasma insulin concentration). The ific and medical basis for identifying pre-
diabetes as a serious health threat is laid out in a Position Statement entitled "The
Prevention or Delay of Type 2 Diabetes" issued jointly by the American Diabetes Association
and the National Institute of Diabetes and Digestive and Kidney Diseases (Diabetes Care
2002; 25:742-749).
Individuals likely to have insulin resistance are those who have two or more of the following
attributes: 1) ovenNeight or obese, 2) high blood pressure, 3) hyperlipidemia, 4) one or more
1St degree relative with a diagnosis of IGT or IFG or type 2 diabetes. Insulin resistance can
be confirmed in these individuals by calculating the HOMA-IR score. For the purpose of this
ion, insulin resistance is defined as the clinical condition in which an individual has a
HOMA-IR score > 4.0 or a HOMA-IR score above the upper limit of normal as defined for the
laboratory ming the glucose and insulin , or values above the 75th percentile of
the reference population.
The term “type 2 diabetes” is defined as the condition in which a subject has a fasting (i.e.,
no caloric intake for 8 hours) blood glucose or serum glucose concentration greater than 125
mg/dL (6.94 mmol/L), when measured at minimum two independent occasions. The
measurement of blood glucose values is a rd procedure in routine l analysis.
Type 2 diabetes is also defined as the condition in which a subject has HbA1c equal to, or
greater than 6.5%, a two hour plasma glucose equal to, or greater than 200 g/dL (11.1
mmol/L) during an oral glucose tolerance test (OGTT) or a random glucose concentration
equal to, or greater than 200 mg/dL (11.1 mmol/L) in conjunction with classic symptoms of
hyperglycaemia or hyperglycaemic crisis. In the absence of unequicoval hyperglycaemia, as
with most diagnostic tests, a test result diagnostic of es should be repeated to rule out
laboratory error. The assessment of HbA1c should be performed using a method certified by
the National Glycohemoglobin Standardization Program (NGSP) and standardized or
2012/062922
traceable to the Diabetes Control and Complications Trial (DCCT) reference assay. If a
OGTT is carried out, the blood sugar level of a diabetic will be in excess of 200 mg of
glucose per dL (11.1 mmol/l) of plasma 2 hours after 75 g of glucose have been taken on an
empty h. In a glucose tolerance test 75 g of glucose are stered orally to the
patient being tested after aminimun of 8 hours, typicaly after 10-12 hours, of g and the
blood sugar level is recorded immediately before taking the glucose and 1 and 2 hours after
taking it. In a healthy subject, the blood sugar level before taking the glucose will be n
60 and 110 mg per dL of plasma, less than 200 mg per dL 1 hour after taking the glucose
and less than 140 mg per dL after 2 hours. If after2 hours the value is between 140 and
200 mg, this is regarded as al glucose tolerance.
The term "late stage type 2 diabetes mellitus" includes patients with a long-standing
duration of diabetes, ary drug failure, indication for insulin therapy and potentially
progression to micro- and macrovascular complications e.g. diabetic nephropathy, or
coronary heart disease (CHD).
The term “type 1 diabetes” is defined as the condition in which a subject has, in the
presence of autoimmunity towards the pancreatic beta-cell (i.e. detection of circulating islet
cell autoantibodies [“type 1A diabetes mellitus”], i.e., at least one of: GAD65 [glutamic acid
decarboxylase-65], ICA [islet-cell cytoplasm], lA—2 [intracytoplasmatic domain of the ne
atase-like protein lA—2], ZnT8 transporter—8] or anti-insulin; or other signs of
automimmunity without the presence of typical circulating autoantibodies [type 18 diabetes],
i.e. as detected through pancreatic biopsy or imaging), a fasting (i.e., no caloric intake for 8
hours) blood glucose or serum glucose concentration greater than 125 mg/dL (6.94 mmol/L).
Type 1 diabetes is also defined as the condition in which a subject has, in the presence of
munity towards the atic beta-cell, HbA1c equal to, or greater than 6.5%, a two
hour plasma glucose equal to, or greater than 200 g/dL (11.1 ) during an oral glucose
tolerance test (OGTT) or a random glucose equal to, or greater than 200 mg/dL (11.1
mmol/L) in conjunction with classic symptoms of hyperglycaemia or hyperglycaemic crisis. In
the absence of uneqicoval hyperglycaemia, as with most diagnostic tests, a test result
diagnostic of diabetes should be repeated to rule out laboratory error. The measurement of
blood glucose values is a standard procedure in e medical analysis.The assessment of
HbA1c should be performed using a method certified by the National Glycohemoglobin
Standardization Program (NGSP) and standardized ortraceable to the Diabetes Control and
Complications Trial (DCCT) reference assay. If a OGTT is d out, the blood sugar level
of a diabetic will be in excess of 200 mg of glucose per dL (11.1 mmol/l) of plasma 2 hours
after 75 g of glucose have been taken on an empty stomach, in the presence of
autoimmunity towards the atic beta cell. In a glucose tolerance test 75 g of glucose
are administered orally to the patient being tested after a minimum of 8 hours, typically, 10-
12 hours, of fasting and the blood sugar level is recorded immediately before taking the
glucose and 1 and 2 hours after taking it. Typically a genetic predisposition is present (e.g.
HLA, INS VNTR and PTPN22), but this is not always the case.
The term ”MODY” (“maturity onset diabetes of the youth”) describes a monogenic form for
diabetes that, according to gene affects, is split into MODY variants, e.g., MODY 1,2.3.4 etc.
The term “LADA” (“latent autoimmune diabetes of adults”) refers to patients that has a
clinical diagnosis of type 2 diabetes, but who is being detected to have autoimmunity towards
the pancreatic beta cell.
The term "HbA1c" refers to the product of a non-enzymatic glycation of the haemoglobin B
chain. lts determination is well known to one skilled in the art. In monitoring the ent of
diabetes mellitus the HbA1c value is of exceptional importance. As its production depends
essentially on the blood sugar level and the life of the erythrocytes, the HbA1c in the sense
of a "blood sugar memory" ts the average blood sugar levels of the preceding 4-6
weeks. Diabetic patients whose HbA1c value is consistently well adjusted by intensive
diabetes treatment (i.e. < 6.5 % of the total haemoglobin in the ), are significantly
better protected against diabetic microangiopathy. For example, metformin on its own
es an average improvement in the HbA1c value in the ic of the order of 1.0 — 1.5
%. This reduction of the HbA1C value is not sufficient in all diabetics to achieve the desired
target range of < 6.5 % and preferably < 6 % HbA1c.
The term "insufficient glycemic control" or "inadequate glycemic control" in the scope of
the t invention means a ion n ts show HbA1c values above 6.5 %,
in particular above 7.0 %, even more preferably above 7.5 %, especially above 8 %.
The “metabolic syndrome”, also called “syndrome X” (when used in the context of a
metabolic disorder), also called the “dysmetabolic syndrome” is a syndrome complex with the
cardinal e being insulin resistance (Laaksonen DE, et al. Am J Epidemiol
2002;156:1070-7). According to the ATP lll/NCEP guidelines (Executive Summary of the
Third Report of the National Cholesterol ion Program (NCEP) Expert Panel on
Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment
Panel lll) JAMA: Journal of the American MedicalAssociation (2001) 285:2486-2497),
WO 07557
diagnosis of the metabolic syndrome is made when three or more of the following risk s
are present:
1. Abdominal obesity, defined as waist circumference > 40 inches or 102 cm in
men, and > 35 inches or 94 cm in women; or with regard to a Japanese ethnicity or
Japanese patients defined as waist ference 2 85 cm in men and 2 90 cm in
women; or othenNise population specific;
2. Triglycerides: 2 150 mg/dL
3 HDL-cholesterol < 40 mg/dL in men and <50 in women
4. Blood pressure 2130/85 mm Hg (SBP 2130 or DBP 2 85)
5 Fasting blood glucose 2 100 mg/dL
The NCEP definitions have been validated (Laaksonen DE, et al. Am J iol. (2002)
156:1070-7). cerides and HDL terol in the blood can also be determined by
standard methods in medical analysis and are described for example in Thomas L (Editor):
"Labor und Diagnose“, TH-Books Verlagsgesellschaft mbH, Frankfurt/Main, 2000.
According to a commonly used tion, hypertension is sed if the systolic blood
pressure (SBP) exceeds a value of 140 mm Hg and diastolic blood pressure (DBP) exceeds
a value of 90 mm Hg. If a patient is suffering from manifest diabetes it is currently
recommended that the systolic blood pressure be reduced to a level below 130 mm Hg and
the diastolic blood pressure be lowered to below 80 mm Hg.
The definitions of NODAT (new onset diabetes after transplantation) and PTMS (post-
transplant metabolic syndrome) follow y that of the American Diabetes Association
diagnostic criteria for type 2 diabetes, and that of the ational Diabetes Federation (lDF)
and the an Heart Association/National Heart, Lung, and Blood Institute, for the
metabolic syndrome. NODAT and/or PTMS are associated with an increased risk of micro-
and macrovascular disease and events, graft rejection, infection, and death. A number of
predictors have been identified as potential risk factors related to NODAT and/or PTMS
including a higher age at transplant, male gender, the pre-transplant body mass index, pre-
lant diabetes, and immunosuppression.
The term "gestational diabetes" (diabetes of pregnancy) denotes a form of the diabetes
which develops during pregnancy and usually ceases again immediately after the birth.
Gestational diabetes is diagnosed by a screening test which often is carried out between the
24th and 28th weeks of pregnancy, but could be conducted at any time during pregnancy, in
particular if previous gestational diabetes has been diagnosed. It is usually a simple test in
which the blood sugar level is measured e.g., one hour after the administration of 50 g of
glucose solution. If this 1 h level is above 140 mg/dl, gestational diabetes is suspected. Final
confirmation may be obtained by a standard glucose tolerance test, for example with 75 g of
glucose; which also serve as a diagnostic test in the absence of the 50 g challenge.
The term "hyperuricemia" denotes a ion of high serum total urate levels. In human
blood, uric acid concentrations n 3.6 mg/dL (ca. 214 umol/L) and 8.3 mg/dL (ca. 494
) are considered normal by the American Medical Association. High serum total urate
levels, or ricemia, are often associated with several maladies. For example, high
serum total urate levels can lead to a type of arthritis in the joints kown as gout. Gout is a
condition created by a build up of monosodium urate or uric acid crystals on the articular
cartilage ofjoints, tendons and surrounding tissues due to elevated concentrations of total
urate levels in the blood stream. The build up of urate or uric acid on these s es
an inflammatory reaction of these tissues. Saturation levels of uric acid in urine may result in
kidney stone formation when the uric acid or urate crystallizes in the kidney. Additionally,
high serum total urate levels are often associated with the so-called metabolic me,
including cardiovascular disease and hypertension.
The term "SGLT2 inhibitor" in the scope of the present invention relates to compounds, in
ular to glucopyranosyl-derivatives, i.e. compounds having a glucopyranosyl-moiety,
which show an inhibitory effect on the sodium-glucose transporter2 (SGLT2), in particular
the human SGLT2 (hSGLT2). The inhibitory effect on hSGLT2 measured as |C50 is
preferably below 1000 nM, even more preferably below 100 nM, most preferably below 50
nM. The tory effect on hSGLT2 can be determined by methods known in the ture,
in ular as described in the application or (pages
23/24), which are incorporated herein by reference in its ty. The term "SGLT2 inhibitor"
also comprises any pharmaceutically able salts thereof, hydrates and solvates thereof,
including the respective crystalline forms.
The terms "treatment" and "treating" comprise therapeutic treatment of patients having
already developed said condition, in particular in manifest form. Therapeutic treatment may
be symptomatic treatment in order to relieve the symptoms of the specific indication or
causal treatment in order to reverse or partially reverse the conditions of the indication or to
stop or slow down progression of the e. Thus the compositions and methods of the
present ion may be used for instance as therapeutic treatment over a period of time as
well as for chronic therapy.
The terms "prophylactically treating , preventivally treating"and "preventing" are used
interchangeably and comprise a treatment of patients at risk to develop a condition
mentioned hereinbefore, thus ng said risk.
The term "tablet" comprises tablets without a coating and tablets with one or more coatings.
Furthermore the "term" tablet comprises tablets having one, two, three or even more layers
and press-coated tablets, wherein each of the beforementioned types of s may be
without or with one or more coatings. The term ”tablet” also comprises mini, melt, chewable,
effervescent and orally disintegrating s.
The terms "pharmacopoe" and "pharmacopoeias" refer to standard pharmacopoeias such
as the “USP 31—NF 26 through Second Supplement” (United States Pharmacopeial
Convention) or the “European Pharmacopoeia 6.3” (European Directorate for the Quality of
Medicines and Health Care, 2000-2009).
Brief ption of the Figures
Figure 1 shows an X-ray powder diffractogram of the crystalline form (l.9X) of the compound
(l.9). Figure 2 shows the thermoanalysis and determination of the melting point via DSC of
the crystalline form (l9.X) of the compound (l.9).
Detailed Description
The t invention provides methods for preventing, slowing the progression of, ng
or treating renal hyperfiltrative injury in a patient. The present invention further provides
methods for ting, slowing the progression of, ng or treating a condition or
disorder selected from the group consisting of iltrative diabetic nephropathy, renal
hyperfiltration, glomerular hyperfiltration, renal allograft hyperfiltration, compensatory
hyperfiltration (e.g. after renal mass reduction by surgery), hyperfiltrative chronic kidney
e, hyperfiltrative acute renal e and compensatory hyperfiltration in association
with obstructive uro/nephropathy or morbid obesity. In the methods of the present invention a
SGLT-2 inhibitor is administered to the patient. In particular, the SGLT-2 inhibitor used in the
context of the present invention is 1-chloro(B-D-glucopyranosyl)[4-((S)-
ydrofuranyloxy)—benzyl]—benzene or a prodrug thereof.
SGLT2 inhibitors represent a novel class of agents that are being developed for the
treatment or improvement in glycemic control in patients with type 2 diabetes.
Glucopyranosyl-substituted benzene derivatives are described in the prior art as SGLT2
inhibitors, for example in WO 28, WO 03/099836, , WO
2006/034489, WO 64033, , , ,
WO 28814, , , , WO
2008/049923, , . The glucopyranosyl-substituted benzene
derivatives are proposed as inducers of urinary sugar excretion and as medicaments in the
ent of diabetes.
Renal filtration and reuptake of glucose contributes, among other mechanisms, to the steady
state plasma glucose concentration and can therefore serve as an antidiabetic target.
Reuptake of filtered glucose across epithelial cells of the kidney proceeds via sodiumdependent
glucose cotransporters (SGLTs) located in the brush-border membranes in the
tubuli along the sodium nt. There are at least 3 SGLT isoforms that differ in their
expression pattern as well as in their physico-chemical ties. SGLT2 is almost
exclusively expressed in the kidney, whereas SGLT1 is expressed additionally in other
s like intestine, colon, skeletal and cardiac muscle. SGLT3 has been found to be a
glucose sensor in titial cells of the intestine without any transport function. Potentially,
other related, but not yet characterized genes, may bute further to renal glucose
reuptake. Under normoglycemia, glucose is completely reabsorbed by SGLTs in the kidney,
whereas the reuptake capacity of the kidney is saturated at glucose concentrations higher
than 10mM, resulting in uria (“diabetes mellitus”). This threshold concentration can be
decreased by SGLT2-inhibition. It has been shown in ments with the SGLT inhibitor
phlorizin that nhibition will partially inhibit the reuptake of glucose from the glomerular
filtrate into the blood leading to a decrease in blood glucose concentrations and to
glucosuria.
In one aspect, a patient in the t of the present invention is an individual showing renal
hyperfiltration or at risk of developing renal hyperfiltration. Such patient is for example an
dual diagnosed or showing diabetes mellitus (see for example Melsom et al. Diabetes
Care 2011; DOI: 10.2337/dc11-0235). Such patient is for example an individual diagnosed or
showing type 1 diabetes us, type 2 diabetes mellitus, MODY, LADA, abetes,
morbid obesity, congenital or acquired obstructive uro/nephropathy, progressive c
kidney disease (CKD) and/or acute renal failure (ARF). Such patient is also for example a
renal transplant recipient, a renal transplant donors, or an unilateral total or partial
nephrectomized patient.
In another aspect, a patient in the context of the present invention is an individual having
glomerularfiltration rate (GFR) equal to or above 125 ml/min/1.73 m2. In a further aspect, a
patient in the context of the present invention is an individual having a GFR equal to or
above 140 ml/min/1.73 m2. The GFR of the individual is ed by a method known in the
art or as described herein.
In one particular aspect, the patient is an individual diagnosed with type 1 es mellitus.
In another particular aspect, the patient is an individual diagnosed with type 2 diabetes
mellitus, MODY, LADA or pre-diabetes. In one aspect, the patient:
(1) is an individual sed of one or more of the conditions selected from the group
consisting of ovenNeight, obesity, visceral obesity and abdominal obesity; or
(2) is an individual who shows one, two or more of the following conditions:
(a) a fasting blood glucose or serum glucose concentration r than 100
mg/dL, in particular greater than 125 mg/dL;
(b) a postprandial plasma glucose equal to or greaterthan 140 mg/dL;
(c) an HbA1c value equal to or greater than 6.0 %, in ular equal to or
greater than 6.5%, in particular equal to or greaterthan 8.0 %;
(3) is an individual wherein one, two, three or more of the following conditions are
present:
(a) y, visceral obesity and/or abdominal obesity,
(b) triglyceride blood level 2 150 mg/dL,
(c) HDL-cholesterol blood level < 40 mg/dL in female ts and < 50 mg/dL in
male ts,
(d) a ic blood pressure 2 130 mm Hg and a diastolic blood pressure 2 85
mm Hg,
(e) a fasting blood glucose level 2 100 mg/dL; or
(4) is an individual with morbid obesity.
Examples of SGLT2 inhibitors are selected from a glucopyranosyl-substituted benzene
derivative of the formula (I)
wherein R1 denotes Cl, methyl or cyano; R2 denotes H, methyl, methoxy or hydroxy and R3
denotes ethyl, ropyl, ethynyl, ethoxy, (R)—tetrahydrofuranyloxy or (S)-
tetrahydrofuranyloxy; or a prodrug of one of the beforementioned SGLT2 inhibitors.
Compounds of the a (I) and methods of their synthesis are described for e in
the following patent applications: , , ,
, , , WO 93610, WO
2008/020011, , , and .
In the above glucopyranosyl-substituted benzene derivatives of the a (I) the following
definitions of the substituents are preferred.
Preferably R1 denotes chloro or cyano; in particular chloro.
Preferably R2 denotes H.
Preferably R3 denotes ethyl, cyclopropyl, ethynyl, (R)—tetrahydrofuranyloxy or (S)-
tetrahydrofuranyloxy. Even more preferably R3 denotes ropyl, ethynyl, (R)-
tetrahydrofuranyloxy or (S)-tetrahydrofuranyloxy. Most preferably R3 s ethynyl,
(R)—tetrahydrofuranyloxy or (S)-tetrahydrofuranyloxy.
For example, glucopyranosyl-substituted benzene derivatives of the formula (I) are selected
from the group of compounds (L1) to (l.11):
2-(4-ethylbenzyl)(B-D-glucopyranosy|)methoxy-benzonitrile,
WO 07557
1-chloro(B-D-glucopyranosyl)[4-((R)-tetrahydrofuranyloxy)—
benzyl]—benzene,
1-chloro(B-D-glucopyranosyl)[4-((S)-tetrahydrofuranyloxy)—
benzyl]—benzene,
1-methy|—2-[4-((R)—tetrahyd rofu ranyloxy)—benzyl]—4-(B-D-glucopyranos-1 -
yl)-benzene,
1-methyl[4-((S)—tetrahyd rofu ranyloxy)—benzyl](B-D-glucopyranos-1 -
yl)-benzene.
A red glucopyranosyl-substituted benzene derivatives of the formula (I) is compound
(l.9).
According to this invention, it is to be understood that the definitions of the above listed
glucopyranosyl-substituted benzene tives of the formula (I) also comprise their
hydrates, so|vates and polymorphic forms f, and prodrugs thereof. With regard to the
compound (l.7) an ageous crystalline form is described in the international patent
application which hereby is incorporated herein in its entirety. With regard
to the compound (l.8), an ageous crystalline form is bed in the international
patent application which hereby is incorporated herein in its entirety. With
regard to the compound (l.9) an advantageous crystalline form is described in the
international patent applciation and which hereby are
incorporated herein in its ty. With regard to the nd (|.11) an advantageous
crystalline form is described in the international patent applciation which
hereby is incorporated herein in its entirety. These crystalline forms possess good solubility
properties which enable a good bioavailability of the SGLT2 inhibitor. Furthermore, the
crystalline forms are physico-chemically stable and thus provide a good shelf-life stability of
the pharmaceutical composition.
For avoidance of any doubt, the disclosure of each of the foregoing documents cited above
in connection with the specified SGLT2 inhibitors is specifically incorporated herein by
reference in its entirety.
A preferred lline form (l.9X) of the nd (l.9) can be characterized by an X-ray
powder diffraction pattern that comprises peaks at 18.84, 20.36 and 25.21 degrees 2(9 (i0.1
degrees 2(9), wherein said X-ray powder ction pattern (XRPD) is made using CuKOd
radiation.
In particular said X-ray powder diffraction pattern comprises peaks at 14.69, 18.84, 19.16,
19.50, 20.36 and 25.21 degrees 2(9 (i0.1 s 2(9), wherein said X-ray powder diffraction
pattern is made using CuKOd radiation.
In particular said X-ray powder diffraction pattern comprises peaks at 14.69, 17.95, 18.43,
18.84, 19.16, 19.50, 20.36, 22.71, 23.44, 24.81, 25.21 and 25.65 degrees 2(9 (i0.1 degrees
2(9), wherein said X-ray powder ction pattern is made using CuKOd radiation.
More specifically, the crystalline form (l.9X) is characterised by an X-ray powder diffraction
pattern, made using CuKal radiation, which comprises peaks at degrees 2(9 (i0.1 degrees
2(9) as contained in Table 1.
Table 1: X-ray powder diffraction n of the crystalline form (I.9X) (only peaks up to
° in 2 ® are listed):
d-value Intensity lllo
WO 07557 2012/062922
Even more specifically, the crystalline form (l.9X) is characterised by an X-ray powder
diffraction n, made using CuKal radiation, which comprises peaks at degrees 29 (:01
degrees 2(9) as shown in Figure 1.
Furthermore the crystalline form (l.9X) is characterised by a melting point of about 149°C i
3°C (determined via DSC; evaluated as temperature; heating rate 10 K/min).The
obtained DSC curve is shown in Figure 2.
The X-ray powder diffraction patterns are ed, within the scope of the present invention,
using a STOE - STADI P-diffractometer in transmission mode fitted with a location-sensitive
detector (OED) and a Cu-anode as X-ray source (CuKocl radiation, 7» = 1,54056 A , 40kV,
40mA). In the Table 1 above the values "2G [°]" denote the angle of diffraction in degrees
and the values "d [A]" denote the specified distances in A n the lattice planes. The
intensity shown in the Figure 1 is given in units of cps (counts per second).
In order to allow for experimental error, the above described 20 values should be considered
accurate to i 0.1 degrees 20, in particular i 0.05 degrees 20. That is to say, when
assessing whether a given sample of crystals of the compound (l.9) is the crystalline form in
accordance with the invention, a 28 value which is experimentally observed for the sample
should be considered identical with a characteristic value described above if it falls within i
0.1 degrees 28 of the characteristic value, in particular if it falls within i 0.05 degrees 28 of
the characteristic value.
The melting point is ined by DSC (Differential Scanning Calorimetry) using a DSC 821
(Mettler Toledo).
In one embodiment, a pharmaceutical composition or dosage form according to the present
invention comprises the nd (l.9), wherein at least 50 % by weight of the compound
(l.9) is in the form of its crystalline form (l.9X) as defined hereinbefore. Preferably in said
composition or dosage form at least 80 % by weight, more preferably at least 90 % by weight
of the compound (l.9) is in the form of its crystalline form (l.9X) as defined before.
Regarding the active pharmaceutical ingredients it can be found that the dissolution
properties of the pharmaceutical composition and dosage form is affected inter alia by the
particle size and particle size distribution of the respective active pharmaceutical ingredient.
In the pharmaceutical composition and pharmaceutical dosage form according to the
invention the active pharmaceutical ingredients preferably have a particle size distribution
such that at least 90 % of the respective active pharmaceutical ingredient particles, with
regard to the distribution by volume, has a particle size smaller than 200 um, i.e. X90 < 200
pm.
In particular, with regard to the glucopyranosyl-substituted benzene derivative of the formula
(I), in particular the compound (l.9) or its crystalline form (l.9X), it was found that the particle
size influence the manufacturability, in particular that too small particles influence the
manufacturability by sticking or filming. On the other hand too large les negatively affect
the dissolution properties of the pharmaceutical ition and dosage form and thus the
bioavailability. In the following preferred ranges of the particle size bution are described.
Therefore, in one aspect, in the ceutical composition and pharmaceutical dosage
form ing to the invention the glucopyranosyl-substituted e tive of the
formula (I), in particular the compound (l.9), preferably its lline form (l9.X), preferably
has a le size distribution (by ) such that at least 90 % of the respective active
pharmaceutical ingredient has a particle size smaller than 200 um, i.e. X90 < 200 um,
preferably X90 3 150 pm. More preferably the particle size distribution is such that X90 3 100
um, even more preferably X90 3 90 pm. In addition the particle size distribution is preferably
such that X90 2 1 pm, more preferably X90 2 5 pm, even more preferably X90 2 10 um.
Therefore preferred particle size butions are such that 1 pm 3 X90 < 200 um, particularly
1 pm 3 X90 3 150 pm, more preferably 5 pm 3 X90 3 150 um, even more preferably 5 pm S
X90 3 100 um, even more preferably 10 pm 3 X90 3 100 pm. A preferred example X90 3 75
um. Another red example is 20 pm 3 X90 3 50 um.
Furthermore in the pharmaceutical composition and pharmaceutical dosage form according
to the invention the glucopyranosyl-substituted benzene derivative of the formula (I), in
particular the compound (l.9), preferably its crystalline form , preferably has a le
size distribution (by volume) such that X50 3 90 pm, more preferably X50 3 75 um, even
more preferably X50 3 50 um, most preferably X50 3 40 pm. In addition the particle size
distribution is preferably such that X50 2 1 pm, more preferably X50 2 5 pm, even more
preferably X50 2 8 pm. Therefore preferred particle size distributions are such that 1 pm 3
X50 3 90 um, particularly 1 pm 3 X50 3 75 pm, more preferably 5 pm 3 X50 3 75 um, even
more preferably 5 pm 3 X50 3 50 pm. A red example is 8 pm 3 X50 3 40 um.
Furthermore in the pharmaceutical composition and pharmaceutical dosage form according
to the invention the glucopyranosyl-substituted benzene derivative of the formula (I), in
particular the compound (l.9), preferably its lline form (l9.X), preferably has a particle
size distribution (by volume) such that X10 2 0.1 pm, more preferably X10 2 0.5 pm, even
more preferably X10 21 pm, in ular X10 2 2 pm.
Therefore a pharmaceutical composition or pharmaceutical dosage form according to this
invention may preferably be characterized by the above specified particle size butions
X90, X50 and/or X10 or one of the following embodiments:
Embodiment GIucopyranosyI-substituted
benzene derivative, in particular of
the compound (|.9)
1 X90 < 200 um
2 1pm 3X90 s 150 pm
3 5umSX9OS150um
10umSX9OS100um
X903150 um
1umsX5OS75 um
_ 5pm$X50$50um
X903150 um
1umsX50375 um
X1020.1um
0 pm
umsX50350 um
X10205 pm
The value X90 refers to the 90% value of the volume distribution measured using a laser
diffractometer. In other words, for the purposes of the present invention, the X90 value
denotes the particle size below which 90% of the quantity of particles is found based on the
volume distribution. Analogously the value X50 refers to the 50% value (median) of the
volume bution ed using a laser diffractometer. In other words, for the es of
the present invention, the X50 value denotes the particle size below which 50% of the
quantity of particles is found based on the volume bution. Analogously the value X10
refers to the 10% value of the volume distribution measured using a laser diffractometer. In
other words, for the purposes of the present invention, the X10 value denotes the particle
size below which 10% of the quantity of particles is found based on the volume distribution.
Preferably all X90, X50, X10 values hereinbefore and hereinafter are by volume and
ined by laser-diffraction method, in particular low angle laser light scattering, i.e.
Fraunhofer diffraction. A red test is described in the mental section. The laser
diffraction method is ive to the volume of a particle and provides a volume-average
particle size, which is equivalent to the weight-average particle size if the density is constant.
The skilled artesian knows that the results of the particle size distribution determination by
one que can be correlated with that from another technique, for example on an
empirical basis by routine experimentation. Alternatively the particle size distribution in the
pharmaceutical composition or dosage form can be determined by microscopy, in particular
electron microscopy or ng on microscopy.
In the following the suitable excipients and carriers in the pharmaceutical compositions
according to the invention are described in further detail.
A pharmaceutical composition according to the invention typically comprises one or more
diluents, one or more disintegrants and optionally one or more binders. Some of the
excipients may have two or more functions at the same time, e.g. act as a filler and a binder.
Suitable diluents ing to the invention are for example, lactose, in particular lactose
drate, ose and tives, such as powdered cellulose, microcrystalline or
silicified microcrystalline cellulose, cellulose acetate, es and derivatives such as
pregelatinized starch, corn starch, wheat starch, rice starch, potato starch, izable maize,
sodium chloride, calcium carbonate, calcium phosphate, particularly dibasic calcium
phosphate, calcium sulphate, dicalcium or tricalcium ate, magnesium carbonate,
magnesium oxide, sugars and tives such as confectioner’s sugar, fructose, sucrose,
dextrates, n, D-sorbitol sulfobutylether B-cyclodextrin, dextrose, polydextrose,
ose, maltose, maltitol, mannitol, maltodextrin, sorbitol, inulin, xylitol, erythritol, isomalt,
kaolin and lactitol. Preferred diluents are lactose monohydrate and microcrystalline cellulose.
Suitable disintegrants according to the invention are for example powdered cellulose,
crospovidone, croscarmellose sodium, docusate sodium, low-substituted hydroxypropyl
cellulose, ium aluminum silicate, microcrystalline cellulose, polacrilin potassium,
sodium starch glycolate, starch, particularly pregelatinized starch and corn starch. A
preferred disintegrant is rmellose sodium.
Any binder usually employed in pharmaceutical compositions may be used in the context of
the instant invention. Binders are for example naturally occurring or partially or totally
synthetic polymers selected from , agar, alginic acid, carbomers, carmellose sodium,
carrageenan, cellulose acetate ate, ceratonia, chitosan, confectionar’s sugar,
copovidone, povidone, cottonseed oil, dextrate, dextrin, dextrose, polydextrose, maltodextrin,
e, ose and derivatives thereof such as microcrystalline cellulose, methylcellulose,
ethylcellulose, hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl
celluloses, carboxymethylcelluloses, hypromelloses (cellulose hydroxypropyl methyl ether),
starch and derivatives thereof, such as pregelatinized starch, hydroxypropylstarch, corn
starch, gelatin, glyceryl behenate, tragacanth, guar gum, hydrogenated vegetable oils, inulin,
poloxamer, polycarbophils, hylene oxide, polyvinylpyrrolidone, copolymers of N-
vinylpyrrolidone and vinyl acetate, polymethacrylates, hylene glycols, alginates such as
sodium alginate, gelatin, sucrose, sunflower oil, zein as well as derivatives and mixtures
f. Preferred binders are microcrystalline ose and hydroxypropyl cellulose.
The pharmaceutical composition according to the present invention may also comprise one
or more lubricants. Suitable ants ing to the invention are stearic acid as well as
salts thereof including talc, sodium stearate, calcium stearate, zinc stearate, magnesium
stearate, sodium stearyl fumarate, glyceryl monostearate, particularly magnesium stearate,
polyethylene glycols, in particular polyethylene glycol with a molecular weight in a range from
about 4400 to about 9000, hydrogenated castor 0", fatty acid, for example fumaric acid, and
salts of fatty acids, in particular the calcium, ium, sodium or pottasium salts thereof,
for example calcium te, calcium stearate, sodium stearyl te or magnesium
stearate (for example (e.g. HyQuaI®, Mallinckrodt), ides such as glyceryl behenate
(Compritol® 888), Dynasan® 118 or Boeson® VP.
The pharmaceutical ition according to the present invention may also comprise one
or more glidants. Suitable glidants according to the ion are silicon dioxide, particularly
colloidal silicon dioxide (e.g. Aerosi|®, Cab-O-Si|®), stearic acid as well as salts thereof
including sodium stearate, calcium stearate, zinc stearate, magnesium stearate, magnesium
silicate, calcium silicate, magnesium trisilicate and talc. Preferred glidants are dal n
dioxide and talc.
In another embodiment, a pharmaceutical composition ing to the instant invention
comprises
Amount
(% by weight)
Active ingredient 0.5 — 25
One or more diluents 65 - 93
One or more disintegrants
Optionally additional additives ad 100 %
In one aspect, the active ient is a compound of the formula (I), for example of the
formula (l.9) or its crystalline form (l.9X).
In another embodiment, a pharmaceutical composition according to the instant invention
comprises
Amount
Active ingredient
One or more diluents
One or more disintegrants
Optionally additional additives ad 100 %
The active ingredient is a compound of the formula (I), for example of the formula (l.9) or its
crystalline form (l.9X).
In another embodiment, a pharmaceutical composition according to the instant invention
comprises
Amount
Active ingredient
Lactose monohydrate
Microcrystalline cellulose
Hydroxypropyl cellulose
Croscarmellose sodium
Optionally additional ves
In one aspect, the active ingredient is a compound of the formula (I), for example of the
formula (l.9) or its crystalline form .
In another embodiment, a pharmaceutical composition according to the instant invention
Amount
(% by weight)
Active ingredient 0.5 — 25
Lactose monohydrate 35 - 90
rystalline cellulose
Hydroxypropyl cellulose
Croscarmellose sodium
Additional additives
The active ingredient is a compound of the formula (I), for e of the formula (l.9) or its
lline form .
In one embodiment, the ratio of said disintegrant to said binder in a pharmaceutical
composition of the present invention is between 1.5:3.5 and 1:1.
In one embodiment, the active ingredient represents 25% or less of the weight of the
ceutical composition. Preferably, the active ingredient represents 0.5% to 25% of the
weight of the pharmaceutical ition. More preferably, the active ingredient represents
1.0% to 20% of the weight of the ceutical composition. Even more preferably, the
active ient represents 2.0% to 15% of the weight of the pharmaceutical composition.
In the following, preferred ranges of the amount of the glucopyranosyl-substituted benzene
derivative to be employed in the pharmaceutical dosage form according to this invention are
described. These ranges refer to the amounts to be administered per day with respect to an
adult t, in particular to a human being, for example of approximately 70 kg body weight,
and can be adapted accordingly with regard to an administration 1, 2, 3, 4 or more times
daily and with regard to other routes of administration and with regard to the age of the
patient. The ranges of the dosage and s are calculated for the active ient.
A preferred amount of the glucopyranosyl-substituted benzene derivative, in particular the
compound (l.9) or its crystalline form (l.9X) is in a range from 0.5 to 100 mg, preferably from
0.5 to 50 mg, even more preferably from 1 to 25 mg, even more preferably 5 to 25 mg,
particularly 10 to 25 mg. Preferred dosages of the glucopyranosyl-substituted benzene
derivative are for example 1 mg, 2 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 20
mg, 25 mg and 50 mg, in particular 10 mg and 25 mg.
A pharmaceutical ition according to the t invention may be comprised in a
, a capsule or a film-coated tablet,
In one embodiment, a tablet comprising a pharmaceutical composition according to the
present invention comprises a lubricant, such as magnesium stearate. Such lubricant may
be present in a concentration of 0.25 — 2 % in said tablet.
In one embodiment, a tablet comprising a pharmaceutical composition according to the
present invention comprises a glidant, such as colloidal silicon dioxide. Such glidant may be
present in a concentration of 0.25 — 2 % in said tablet.
A tablet according to the invention may be film-coated. Typically a film coat ents 2-5%
by weight of the total composition and comprises preferably a film-forming agent, a
plasticizer, a glidant and optionally one or more pigments. An ary coat composition
may comprise hydroxypropylmethyl-cellulose (HPMC), polyethylene glycol (PEG), talc,
titanium dioxide and ally iron oxide, including iron oxide red and/or yellow.
In one ment, the pharmaceutical dosage form according to the invention has
dissolution properties such that after 45 minutes at least 75 %, preferably at least 90 % by
weight of the pharmaceutical active ingredient is dissolved. In another embodiment after 30
s at least 75 %, preferably at least 90 % by weight of the pharmaceutical active
ingredien is dissolved. In another embodiment after 15 minutes at least 75 %, preferably at
least 90 % by weight of the pharmaceutical active ingredient is dissolved. The dissolution
properties can be determined in a standard dissolution test, for example as described in
pharmacopoeias, such as the USP31-NF26 82, chapter 711 (dissolution).
In one ment, the pharmaceutical dosage form according to the invention has
disintegration properties such that within 40 minutes, alternatively within 30 minutes,
ably within 20 minutes, more ably within 15 minutes the pharmaceutical dosage
form is disintegrated. The disintegration properties can be determined in a standard
disintegration test, for example as described in pharmacopoeias, such as the USP31-NF26
82, chapter 701 (disintegration).
In one embodiment, the pharmaceutical dosage form according to the invention has a high
content uniformity, preferably within a range from 85 to 115 %, more preferably from 90 to
110 %, even more preferably from 95 to 105 % by weight with regard to the pharmaceutical
ingredient. The content uniformity can be determined in a standard test using for example
randomly 10 selected pharmaceutical dosage forms, for example as described in
pharmacopoeias.
A dosage form according to this invention, such as a tablet, capsule or film-coated tablet,
may be prepared by s well-known to the one skilled in the art.
Suitable methods of manufacturing a tablet e compression of the pharmaceutical
composition in the form of a powder, i.e. direct compression, or compression of the
pharmaceutical composition in the form of granules, and if needed with additional ents.
Granules of the pharmaceutical ition according to the invention may be prepared by
methods well-known to the one d in the art. Preferred s for the granulation of the
active ingredients together with the ents include wet granulation, for example high
shear wet granulation and fluidized bed wet ation, dry granulation, also called roller
compaction.
WO 07557
In the wet granulation process the granulation liquid are the solvent alone or a preparation of
one or more binders in a solvent or mixture of solvents. Suitable binders are described
hereinbefore. Examples are hypromellose, hydroxypropyl cellulose, povidone and
copovidone. Suitable solvents are for example purified water, ethanol, methanol,
isopropanol, e, preferably purified water, including mixtures thereof. The solvent is a
volatile component, which does not remain in the final product. The one or more active
ingredients and the other excipients, in ular the one or more diluents and the one or
more disintegrants, usually with ion of the lubricant, are premixed and granulated with
the ation liquid, for example using a high shear granulator. The wet granulation step is
usually followed by one or more drying and sieving steps. For example a drying oven or a
fluid bed dryer can then be used for .
The dried granules are sieved h an appropriate sieve. After optional addition of the
other excipients, in particular disintegrant, binder, filler and/or glidant, with exception of the
lubricant the mixture is blended in a suitable blender, for example a free fall blender, followed
by addition of the one or more lubricants, for example magnesium stearate, and final
blending in the blender.
An exemplary wet granulation process for making a pharmaceutical composition according to
the instant invention ses the steps of:
(1) Premixing the active ingredient and the main portion of the excipients including the
binder in a mixer to obtain a pre-mixture;
(2) granulating the pre-mixture of step (1) by adding the granulation , preferably
purified water;
(3) drying the granules of step (2) in a fluidized bed dryer or a drying oven;
(4) optionally dry sieving of the dried granules of step (3);
(5) mixing the dried granules of step (4) with the remaining excipients like , binder,
disintegrant and/or glidant in a mixer to obtain the main mixture;
(6) mixing the main mixture of step (5) with the lubricnat in a mixer to obtain the final
mixture;
(7) ing the final mixture of step (6) by compressing it on a suitable tablet press to
produce s cores;
(8) optionally film-coating of the tablet cores of step (7) with a non-functional coat.
The present ion also provides a pharmaceutical composition obtainable by the above
process.
An ary direct compression process according to the present ion for making a
pharmaceutical composition comprises the steps of:
(1) Premixing the active ingredient and the main portion of the excipients in a mixer to
obtain a pre-mixture;
(2) optionally dry screening the pre-mixture through a screen in order to segregate
cohesive les and to improve t uniformity;
(3) mixing the pre-mixture of step (1) or (2) in a mixer, optionally by adding ing
excipients to the mixture and continuing mixing;
(4) tableting the final e of step (3) by compressing it on a suitable tablet press to
produce the tablet cores;
(5) optionally film-coating of the tablet cores of step (4) with a non-functional coat.
The present invention also provides a pharmaceutical composition obtainable by the above
process.
An exemplary dry granulation process according to the present invention for making a
pharmaceutical composition comprises the steps of:
(1) mixing the active ient or a pharmaceutically able salt thereof with either
all or a portion of the excipients in a mixer;
(2) compaction of the mixture of step (1) on a suitable roller compactor;
(3) reducing the ribbons obtained during step (2) to small granules by suitable milling or
sieving steps;
(4) optionally mixing the granules of step (3) with the remaining excipients in a mixer to
obtain the final mixture;
(5) tabletting the es of step (3) or the final mixture of step (4) by compressing it on
a suitable tablet press to produce the tablet cores;
(6) optionally film-coating of the tablet cores of step (5) with a non-functional coat.
In one embodiment, the size of the granules according to the present invention is in the
range from 25 to 800 pm, for e from 40 pm to 500 pm. The size of the granules may
be ed via sieve analysis, for example with a sonic sifter. In one embodiment, at least
80 %, at least 90 %, or at least 95 % by weight of the granules is in the given range.
When this invention refers to patients requiring treatment or prevention, it relates primarily to
treatment and prevention in humans, but the pharmaceutical composition may also be used
accordingly in veterinary medicine in mammals. In the scope of this invention adult patients
are preferably humans of the age of 18 years or older. Also in the scope of this invention,
patients are adolescent humans, i.e. humans of age 6 to 17 years, for example 10 to 17
years, preferably of age 13 to 17 years.
As described hereinbefore by the administration of the pharmaceutical composition
ing to this invention and in particular in view of the high SGLT2 inhibitory activity of the
SGLT2 inhibitors therein, excessive blood glucose is excreted through the urine of the
patient, so that no gain in weight or even a reduction in body weight may . Therefore, a
treatment or prophylaxis according to this invention is ageously suitable in those
patients in need of such treatment or prophylaxis who are diagnosed of one or more of the
conditions selected from the group consisting of ovenNeight and obesity, in particular class I
y, class II obesity, class III obesity, morbid obesity, visceral obesity and abdominal
obesity. In addition a treatment or prophylaxis according to this ion is advantageously
suitable in those patients in which a weight increase should preferably be avoided. The
pharmaceutical composition as well as the methods according to the t invention allow
a reduction of the HbA1c value to a desired target range, for example < 7 % and preferably
< 6.5 %, for a higher number of patients and for a longer time of therapeutic treatment
compared with a corresponding monotherapy or a therapy using only two of the combination
partners.
The ceutical composition according to this invention and in particular the SGLT2
inhibitor therein exhibits a very good efficacy with regard to glycemic control, in particular in
view of a reduction of fasting plasma e, postprandial plasma e and/or
glycosylated hemoglobin (HbA1c). By administering a pharmaceutical composition according
to this ion, a reduction of HbA1c equal to or greater than preferably 0.5 %, even more
preferably equal to or greater than 1.0 % can be achieved and the reduction is particularly in
the range from 1.0 % to 2.0 %.
Furthermore, the method and/or use according to this ion is advantageously applicable
in those patients who show one, two or more of the following conditions:
(a) a fasting blood glucose or serum glucose concentration greater than 100 mg/dL, in
particular greater than 125 mg/dL;
(b) a postprandial plasma glucose equal to or greaterthan 140 mg/dL;
(c) an HbA1c value equal to or greater than 6.0 %, equal to or greater than 6.5 %, equal to
or greater than 7.0 %, equal to or greater than 7.5 %, or equal to or greater than 8.0
In the following preferred ranges of the amount of the SGLT2 inhibitor to be employed in the
ceutical composition and the methods and uses according to this invention are
described. These ranges refer to the amounts to be administered per day with respect to an
adult patient, in particular to a human being, for e of approximately 70 kg body weight,
and can be adapted accordingly with regard to an administration 1, 2, 3, 4 or more times
daily and with regard to other routes of administration and with regard to the age of the
patient.
Within the scope of the present invention, the pharmaceutical composition is ably
administered orally. Other forms of administration are possible and described hereinafter.
Preferably the one or more dosage forms comprising the SGLT2 inhibitor is oral or usually
well known.
In general, the amount of the SGLT2 tor in the pharmaceutical composition and
methods ing to this invention is preferably the amount usually recommended for a
monotherapy using said SGLT2 inhibitor.
The preferred dosage range of the SGLT2 inhibitor is in the range from 0.5 mg to 200 mg,
even more preferably from 1 to 100 mg, most preferably from 1 to 50 mg per day. The oral
administration is preferred. Therefore, a pharmaceutical composition may comprise the
hereinbefore ned amounts, in particularfrom 1 to 50 mg or 1 to 25 mg. Particular
dosage strengths (e.g. let or capsule) are for example 1, 2.5, 5, 7.5, 10, 12.5, 15, 20,
or 50 mg, in particular 10 mg or 25 mg of the SGLT2 inhibitor, such as a compound of the
formula (I), in ular of the compound (l.9) or its crystalline form (l.9X). The application of
the active ingredient may occur up to three times a day, preferably one or two times a day,
most preferably once a day.
The hereinbefore and hereinafter bed methods and uses are employed by
administering a SGLT2 inhibitor, in particular the compound (l.9) to the patient. Most
preferably a pharmaceutical composition comprising the SGLT2 inhibitor, in particularthe
compound (l.9), is administered. An oral stration is preferred.
In one embodiment of the methods and uses according to the present invention the SGLT2
inhibitor, in particularthe compound (l.9) is the only active pharmaceutical ingredient
administered to the patient. Thus the methods and uses relate to a mono-therapy.
In another embodiment of the methods and uses according to the present invention the
SGLT2 inhibitor, in particular the nd (l.9), is administered to the patient in
combination with one or more other active pharmaceutical ingredients. Thus the methods
and uses relate to a combination therapy. Preferably the other active pharmaceutical
ingredient is a medicamentforthe treatment of diabetes mellitus, in particular type 1 es
mellitus or type 2 diabetes mellitus. Therefore the methods and uses according to the
present invention also relate to a combination therapy with one or more other antidiabetics.
The other active pharmaceutical ingredient as a medicament for the treatment of diabetes
us is preferably selected from the group consisting of metformin, a DPPIV inhibitor, an
insulin, a PPARgamma agonist, a GLP-1 or agonist, a glinide, a sulfonylurea or an
alpha-glucosidase blocker, including combinations thereof. Specific examples of other
pharmaceutical ingredients are min, linagliptin, repaglinide, liraglutide, pioglitazone
and glimepirid. Combinations of a SGLT2 inhibitor and an antidiabetic active pharmaceutical
ient are described for example in .
The methods and uses according to the present invention may be of particular advantage in
those patients who are ated with an antidiabetic medicament and who have a risk to
develop hyperfiltration or who are diagnosed of having hyperfiltration. The co-administration
of a SGLT2 inhibitor, in particularthe compound (l.9), in combination with the other
antidiabetc may allow to treat hyperfiltration, including to lower the risk of developing
hyperfiltration, while lowering the blood-glucose levels through excretion of glucose via the
urine and thus having the opportunity to lower the dosage of the other antidiabetic
medicament. Further advantage of the co-administration of the SGLT2 tor is that a
weight loss and/or a reduction of body fat may be achieved or an increase of weight and/or
body fat which would be provoked by the other antidiabetic may be prevented or attenuated.
In addition by using the SGLT2 inhibitor the blood pressure may be lowered which is of
particular age in patients having an elevated risk of high blood re or being
sed of having a high blood pressure.
The SGLT2 inhibitor, in particular the nd (l.9), and the other active pharmaceutical
ingredient, in particular an antidiabetic, may be formulated into one pharmaceutical
composition for combined administration or may be formulated into separate pharmaceutical
compositions for combined or separate administration.
The term metformin includes its salts, such as metformin hloride. Furthermore
min may be comprised in a pharmaceutical composition for immediate e, for
modified release, sustained release or for extended release. Metformin may be administered
orally using pharmaceutical compositions, dosages and administration schemes as known in
the prior art. A preferred dosage range for metformin is 500 to 2000 mg once or twice daily,
for e 500 mg, 850 mg or 1000 mg, preferably once or twice daily. In the methods and
uses according to the present invention the SGLT2 inhibitor, in particular the compound (l.9),
and metformin may be administered in ation, for example simultaneously, and when
they are administered in alternation, for example successively in separate formulations.
Methods for the combined stration of a SGLT2 inhibitor and metformin are described
for example in . Pharmaceutical compositions comprising a SGLT2
inhibitor, in particular the compound (l.9), and metformin are described in .
Preferred dosages of the combination compound (l.9)/ metformin are for example 5 mg/ 500
mg, 12.5 mg/ 500 mg, 5 mg/ 850 mg, 12.5 mg/ 850 mg, 5 mg/1000 mg and 12.5 mg/1000
mg.
The DPPIV inhibitor may be selected from the group consisting of linagliptin, sitagliptin,
saxagliptin, vildagliptin, alogliptin, denagliptin, melogliptin, carmegliptin, iptin,
iptin, gosogliptin, anagliptin, gemigliptin and bisegliptin. The DPPIV tor may be
administered orally using pharmaceutical compositions, dosages and administration
schemes as known in the prior art. A preferred DPPIV inhibitor is linagliptin. As linagliptin is
primarily excreted by bile and the gut a higher safety in patients with renal conditions or
dysfunction is seen. Therefore a combination of the compound (l.9) with linagliptin is of
particular st in the methods and uses according to this invention. A preferred dosage
range for linagliptin is 0.5 to 20 mg once or twice daily, for example 0.5 mg, 1 mg, 2.5 mg,
mg or 10 mg, preferably once daily. In the methods and uses ing to the present
invention the SGLT2 inhibitor, in particular the compound (l.9), and the DPPIV tor, for
e linagliptin, may be administered in combination, for example simultaneously, and
when they are administered in alternation, for e successively in separate formulations.
Methods for the combined administration of a SGLT2 inhibitor and a DPPIV inhibitor are
described for e in . Pharmaceutical compositions comprising a
SGLT2 inhibitor, in ular the compound (l.9), and the DPPIV inhibitor, for example
linagliptin, are described in . red dosages of the combination
compound (l.9)/ linagliptin are for e 10 mg/ 5 mg, 12.5 mg/ 5 mg and 25 mg/ 5 mg.
In addition the methods and uses according to the present invention relate to an
administration of the SGLT2 inhibitor, in particularthe nd (l.9), and the DPPIV
inhibitor, for example linagliptin, in combination or alternation with another active
pharmaceutical ingredient for the treatment of diabetes mellitus. An example of another
active pharmaceutical ient is metformin. Combinations of an SGLT2 inhibitor, a DPPIV
inhibitor and a third active pharmaceutical ingredient are described in the .
The PPARgamma agonist is preferably a thiazolidindione, in ular pioglitazone or
rosiglitazone. The term "pioglitazone" as employed herein refers to pioglitazone, including its
enantiomers, mixtures thereof and its te, or a pharmaceutically acceptable salt
thereof such as the hydrochloride salt. The term "rosiglitazone" as employed herein refers to
rosiglitazone, including its enantiomers, mixtures thereof and its racemate, or a
pharmaceutically acceptable salt thereof such as the maleate salt.
The term "insulin" in the scope of the present invention relates to insulin and insulin analogs
being used in the therapy of patients, in particular humans, which includes normal n,
human insulin, insulin derivatives, zinc insulins and n analogues, ing formulations
thereof with modified release profiles. in particular as used in the therapy of humans. The
term "insulin" in the scope of the present invention covers the following types of insulins:
- rapid-acting insulins,
- short-acting insulins,
- intermediate-acting insulins,
- long-acting insulins,
and es thereof, for e mixtures of short- or rapid-acting insulins with long-acting
insulins. The term "insulin" in the scope of the present invention covers ns which are
administered to the patient via injection, via infusion, including pumps, via inhalation, via oral,
via ermal or other routes of administration. es of insulins are regular insulin or
human insulin, NPH insulin, also known as Humulin N, Novolin N, Novolin NPH and
isophane insulin, lente insulins, such as Semilente or Monotard, insulin glargine, insulin
detemir or n degludec, insulin lispro PEGylated, ed n glargine.
The term "GLP-1 receptor agonist" in the scope of the present invention includes, without
being limited, exogenous GLP-1 (natural or synthetic), GLP-1 analogues and other
substances (whether peptidic or non-peptidic, e.g. small molecules) which e signalling
through the GLP-1 receptor. The exogenous GLP-1 includes natural and synthetic GLP-1, in
particular human GLP-1. The GLP-1 analogues include longer acting analogues also which
are resistant to or have d susceptibility to enzymatic degradation, for example by
DPP-4 and/or NEP 24.11. Examples of GLP-1 analogues are selected from the group
consisting of exenatide (exendin-4); exenatide LAR (long acting e formulation of
exenatide); liraglutide; lutide; semaglutide; albiglutide; lixisenatide; dulaglutide; and
the PEGylated GLP-1 compound comprising the amino acid sequence according to the claim
1 of (the disclosure of which is incorporated herein) and the GLP-1
derivative comprising the amino acid sequence according to SEQ ID NO:21 as disclosed in
the (the disclosure of which is incorporated herein).
Combinations of an insulin and a GLP-1 receptor agonist, in particular a GLP-1 analog, may
be used in combination with the SGLT-2 inhibitor, in particularthe compound (l.9), in the
methods and uses ing to this invention also.
Examples of glinides are repaglinide and nateglinide. Examples of sulfonylureas are
glibenclamide, tolbutamide, glimepiride, glipizide, glyburide, gliclazide. Examples of lucosidase
blockers are miglitol, acarbose and voglibose.
According to a first embodiment a manufacture comprises (a) a pharmaceutical composition
comprising a SGLT2 inhibitor according to the present invention and (b) a label or package
insert which comprises instructions that the medicament is to be administered.
The desired dose of the pharmaceutical composition according to this invention may
conveniently be presented in a once daily or as divided dose stered at appropriate
intervals, for example as two, three or more doses per day.
The pharmaceutical composition may be formulated for oral, rectal, nasal, topical (including
buccal and sublingual), transdermal, vaginal or eral (including intramuscular, sub-
cutaneous and intravenous) administration in liquid or solid form or in a form suitable for
administration by inhalation or lation. Oral administration is preferred. The ations
may, where appropriate, be conveniently presented in discrete dosage units and may be
prepared by any of the s well known in the art of pharmacy. All methods include the
step of bringing into ation the active ingredient with one or more pharmaceutically
acceptable carriers, like liquid carriers or finely divided solid carriers or both, and then, if
necessary, shaping the product into the desired formulation.
The ceutical composition may be formulated in the form of tablets, granules, fine
granules, powders, capsules, caplets, soft capsules, pills, oral ons, syrups, dry syrups,
chewable tablets, troches, effervescent tablets, drops, suspension, fast dissolving tablets,
oral fast-dispersing tablets, etc..
The pharmaceutical composition and the dosage forms ably comprises one or more
pharmaceutical able carriers which must be "acceptable" in the sense of being
compatible with the other ingredients of the formulation and not deleterious to the recipient
thereof. Examples of pharmaceutically able carriers are known to the one skilled in the
art.
WO 07557 2012/062922
Pharmaceutical itions suitable for oral administration may conveniently be presented
as discrete units such as capsules, including soft gelatin capsules, cachets or tablets each
containing a predetermined amount of the active ingredient; as a powder or granules; as a
solution, a suspension or as an emulsion, for example as syrups, elixirs or self-emulsifying
delivery systems (SEDDS). The active ients may also be presented as a bolus,
ary or paste. Tablets and capsules for oral administration may contain conventional
excipients such as binding agents, fillers, lubricants, disintegrants, or wetting agents. The
tablets may be coated according to methods well known in the art. Oral liquid preparations
may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions,
syrups or elixirs, or may be presented as a dry product for constitution with water or other
suitable e before use. Such liquid preparations may contain conventional additives
such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include
edible oils), or preservatives.
The pharmaceutical composition according to the invention may also be formulated for
parenteral administration (e.g. by injection, for example bolus injection or continuous
infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small
volume infusion or in multi-dose containers with an added preservative. The compositions
may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles,
and may contain formulatory agents such as suspending, stabilizing and/or dispersing
. Alternatively, the active ingredients may be in powder form, obtained by aseptic
isolation of sterile solid or by lyophilisation from solution, for constitution with a suitable
vehicle, e.g. sterile, pyrogen-free water, before use.
ceutical itions suitable for rectal administration wherein the carrier is a solid
are most ably presented as unit dose suppositories. Suitable rs e cocoa
butter and other materials commonly used in the art, and the suppositories may be
conveniently formed by admixture of the active compound(s) with the softened or melted
carrier(s) ed by chilling and shaping in moulds.
The ceutical compositions and methods according to this invention show
advantageous effects in the treatment and prevention of those diseases and conditions as
described hereinbefore. Advantageous effects may be seen for example with respect to
cy, dosage strength, dosage frequency, pharmacodynamic properties, pharmacokinetic
properties, fewer adverse s, convenience, compliance, etc..
Methods for the manufacture of SGLT2 tors according to this invention and of prodrugs
thereof are known to the one skilled in the art. Advantageously, the nds according to
this invention can be prepared using synthetic methods as described in the literature,
ing patent applications as cited hereinbefore. Preferred methods of manufacture are
described in the and . With regard to compound (l.9) an
advantageous crystalline form is described in the international patent ation
and which hereby is incorporated herein in its entirety.
Any of the above mentioned pharmaceutical compositions and methods within the scope of
the invention may be tested by animal models known in the art.
Pharmaceutical compositions and s according to this invention can be tested in
genetically hyperinsulinemic or diabetic animals like db/db mice, ob/ob mice, Zucker Fatty
(fa/fa) rats or Zucker Diabetic Fatty (ZDF) rats. In addition, they can be tested in animals with
experimentally induced diabetes like HanWistar or Sprague Dawley rats pretreated with
streptozotocin.
2012/062922
Pharmacological Examples
The following examples show the beneficial effect on glycemic control and hyperfiltration of
the ceutical compositions according to the present invention. Preferably the SGLT-2
inhibitor is 1-chloro(B-D-glucopyranosy|)[4-((S)—tetrahydrofuranyloxy)—benzyl]—
benzene, preferably in the crystalline form (l.9X).
Example 1: Treatment of iltration
In clinical studies g for ent lengths of time (e.g. 1 day to 24 months) the success
of the treatment in ts with hyperfiltration is checked by determining the change in
glomerularfiltration rate (GFR) after treatment with the SGLT-2 tor under controlled
conditions of euglycaemia and hyperglycaemia. Subjects are administered 25 mg of the
SGLT-2 inhibitor once daily.
A significant change in GFR in patients with hyperfiltration, during or at the end of the study,
compared with the initial value or compared with a placebo group, or a group given a
different y, proves the efficacy of a ceutical composition according to the
invention in the treatment of hyperfiltration. The GFR is ined as described herein.
Additional parameters of renal on may also be measured. These include:
- Change in renal hemodynamic function: Effective Renal Plasma Flow (ERPF), Renal
Blood Flow (RBF), Filtration Fraction (FF) and Renal Vascular Resistance (RVR);
- Change in systemic hemodynamic function: Mean al Pressure
(MAP) and arterial stiffness;
- Change in circulating levels of ors involved in Renin-Angiotensin-Aldosterone
System (RAAS) activation and markers of sympathetic activity;
- Change in urinary measurements of nitric oxide, prostanoids and albumin excretion.
The parameters are determined using techniques known in the art.
Examples of Formulations
The following examples of formulations, which may be obtained analogously to methods
known in the art, serve to illustrate the present invention more fully without restricting it to the
contents of these examples. The term "active substance" denotes a SGLT-2 inhibitor
according to this invention, ally a compound of the formula (I), for example a
compound of the formula (l.9) or its crystalline form (l.9X).
The active pharmaceutical ingredient or active sustance, i.e. the compound (l.9), preferably
in the crystalline form (l.9X), is milled with a suitable mill like pin- orjet-mill in order to obtain
2012/062922
the desired particle size distribution before manufacturing of the pharmaceutical composition
or dosage form.
Examples of typical particle size distribution values X90, X50 and X10 for the red active
pharmaceutical ingredient according to the invention are shown in the table below.
Typical particle size distribution s
Active Active
substance substance
Batch 1 Batch 2
Example 1: Dry ampoule containing 50 mg of active nce per 10 ml
Composition:
Active substance 50.0 mg
Mannitol 50.0 mg
water for injections ad 10.0 ml
Preparation:
Active substance and mannitol are dissolved in water. After packaging the solution is freeze-
dried. To produce the solution ready for use, the product is dissolved in water for injections.
Example 2: Dry e containing 25 mg of active substance per 2 ml
Composition:
Active substance 25.0 mg
Mannitol 100.0 mg
water for injections ad 2.0 ml
Preparation:
Active substance and mannitol are dissolved in water. After packaging, the solution is freeze-
dried. To produce the on ready for use, the product is dissolved in water for injections.
Example 3: Tablet containing 50 mg of active substance
_ 44 _
Composition:
(1 ) Active substance 50.0 mg
(2) Mannitol 98.0 mg
(3) Maize starch 50.0 mg
(4) Polyvinylpyrrolidone 15.0 mg
(5) Magnesium stearate 2.0 mg
215.0 mg
Preparation:
(1), (2) and (3) are mixed together and granulated with an aqueous on of (4). (5) is
added to the dried granulated al. From this mixture tablets are pressed, biplanar,
faceted on both sides and with a dividing notch on one side.
Diameter of the tablets: 9 mm.
Example 4: Capsules containing 50 mg of active substance
Composition:
(1 ) Active substance 50.0 mg
(2) Dried maize starch 58.0 mg
(3) Mannitol 50.0 mg
(4) ium stearate 2.0—mg
160.0 mg
Preparation:
(1) is triturated with (3). This trituration is added to the e of (2) and (4) with vigorous
mixing. This powder mixture is packed into size 3 hard gelatin capsules in a capsule filling
Example 5: Tablets containing 2.5mg, 5mg, 10mg, 25mg, 50mg of active substance
‘ ctive substance
et granulation
active substance 2.5000 5.000 10.00 25.00 50.00
Lactose
40.6250 81.250 162.50 113.00 226.00
Monohydrate
Microcrystalline
12.5000 25.000 50.00 40.00 80.00
Cellulose
Hyd roxypropyl 1.8750 3.750 7.50
Croscarmellose
1.2500 2.500 5.00
Purified Water
Dry Adds
Microcrystalline
3.1250 6.250 12.50 10.00 20.00
Cellulose
Colloidal silicon
0.3125 0.625 1.25 1.00 2.00
9-. o5. 0. CD
Magnesium stearate 0.3125 0.625 1.25 1.00 2.00
otal core 62.5000 125.000 250.00 200.00 400.00
Film Coating
Film coating system 2.5000 4.000 7.00
Purified Water
65.000 129.000 257.00 206.00 409.00
Examgle 6: Manufacturing process for s
Step EQUIPMENT MATERIALS OPERATION lN-PROCESS
CONTROLS
1 Screen, Active substance
r and
high shear
granulator Hyd roxypropyl
Cellulose (screened)
Croscarmellose
Sodium
Part of
Microcrystalline
Cellulose PH102
Monohydrate
2 High shear Purified Water —>
GRANULATE
granulator
3 Fluid bed drier DISCHARGE LOD S 2.0% at
ONTO DRYER 100°C
AND DRY
2012/062922
4 Mill (—|DRY MILL
Mill, blender Colloidal n
Dioxide +
Microcrystalline MIX
Cellulose (PH102)
6 Mill, blender Maonesium Stearate MIX
Final tablet
blend
7 Tablet press Tablet weight,
COMPRESS height, crushing
INTO strength,
TABLETS friability,
disintegration
|(—Core tablets
8 Propeller Suspend film-coating —> FILM
Stirrer system in water and COATING
Drum coater mix I(—
Final film Tablet weight,
coated tablets height, crushing
strength,
disintegration
Example 7: Pharmaceutical composition containing other fillers
Copovidone is dissolved in purified water at ambient temperature to produce a granulation
liquid. A glucopyranosyl-substituted benzene derivative according to the present invention,
mannitol, pregelatinized starch and corn starch are d in a suitable mixer, to produce a
pre-mix. The pre-mix is ned with the granulation liquid and subsequently granulated.
The moist granulate is sieved through a suitable sieve. The ate is dried at about 60 °C
inlet air temperature in a fluid bed dryer until a loss on drying value of 1-4 % is obtained. The
dried granulate is sieved through a sieve with a mesh size of 1.0 mm.
Magnesium te is passed through a sieve for delumping and added to the granulate.
Subsequently the final blend is produced by final blending in a suitable blender for three
s and compressed into tablet cores.
2012/062922
Hydroxypropyl methylcellulose, polyethylene glycol, talc, titanium dioxide and iron oxide are
suspended in purified water in a le mixer at ambient temperature to produce a coating
suspension. The tablet cores are coated with the coating suspension to a weight gain of
about 3 % to produce film-coated tablets. The following formulation variants can be obtained:
mg] mg] mg] mg] mg]
Ingredient
tablet tablet tablet tablet tablet
‘ ctive substance 2.5 5.0 10.0 25.0 50.0
ol 133.4 130.9 125.9 110.9 221.8
Pregelatinised starch 18.0 18.0 18.0 18.0 36.0
Maize starch 18.0 18.0 18.0 18.0 36.0
Copovidone 5.4 5.4 5.4 5.4 10.8
Magnesium stearate 2.7 2.7 2.7 2.7 5.4
Film coat 5.0 5.0 5.0 5.0 10.0
370.0
Example 8: Pharmaceutical composition containg other disintegrant
Copovidone is dissolved in purified water at ambient temperature to produce a granulation
. An glucopyranosyl-substituted benzene derivative according to the present invention,
mannitol, pregelatinized starch and corn starch are blended in a suitable mixer, to produce a
pre-mix. The pre-mix is moistened with the granulation liquid and subsequently granulated.
The moist granulate is sieved through a suitable sieve. The granulate is dried at about 60 °C
inlet air temperature in a fluid bed dryer until a loss on drying value of 1-4 % is obtained. The
dried granulate is sieved through a sieve with a mesh size of 1.0 mm.
Crospovidone is added to the dried granulate and mixed for 5 s to produce the main
blend. Magnesium te is passed through a sieve for delumping and added to main
blend. Subsequently the final blend is produced by final blending in a suitable blender for
three minutes and compressed into 8 mm round tablet cores with a compression force of 16
Hydroxypropyl methylcellulose, polyethylene glycol, talc, um dioxide and iron oxide are
suspended in purified water in a suitable mixer at t temperature to produce a coating
suspension. The tablet cores are coated with the coating suspension to a weight gain of
about 3 % to produce film-coated s. The ing formulation variants can be obtained:
mg I mg I mg I mg I mg I
Ingredient
tablet tablet tablet tablet tablet
‘ ctive substance 2.5 5.0 10.0 25.0 50.0
ol 127.5 125.0 120.0 105.0 210.0
Microcrystalline Cellulose 39.0 39.0 39.0 39.0 78.0
Crospovidone 2.0 2.0 2.0 2.0 4.0
Copovidone 5.4 5.4 5.4 5.4 10.8
Magnesium stearate 3.6 3.6 3.6 3.6 7.2
Film coat 5.0 5.0 5.0 5.0 10.0
370.0
The tablet hardness, the friability, the content uniformity, the disintegration time and the
dissolution properties are determined as described hereinbefore.
Example 9: Direct compression formulation
1. Screen the active ient, rystalline cellulose, croscarmellose.sodium and either
hydroxypropyl cellulose or hylene glycol powder through a 20 mesh hand screen.
2. Add the above items into the high shear mixer and mix for two minutes.
3. Make a premix (~1/1) of the lactose and colloidal silicon dioxide.
4. Screen the premix through a 20 mesh hand screen and add to the mixer.
5. Screen the remaining lactose through a 20 mesh hand screen and add to the mixer.
6. Mix in components in the mixer for2 minutes.
7. Screen the magnesium stearate through a 30 mesh hand screen and add to the mixer.
8. Mix for 1 minute 30 seconds to obtain the final blend.
9 Tabletting of the final blend on a suitable tabletting press.
10. Optionally film coating of the tablet cores.
_ mg I mg I mg I mg I mg I
lngredlent
tablet tablet tablet tablet tablet
Microcrystalline Cellulose 12.5000 25.000 50.00 80.0 160.0
Polyethylene glycol 10.0 20.0
Croscarmellose sodium 1.2500 2.500 5.00 16.0
Hydroxypropyl cellulose 1.8750 3.750 7.50
Colloidal Silicon dioxide 0.3125 0.625 1.25 1.0 2.0
ium stearate 0.3125 0.625 1.25 2.0 4.0
Film coat 2.5000 4.000 7.00
Purified water
65.000 129.000 257.00 206.00 409.00
Examgle 10: Tablets containing 0.5mg, 5mg, 25mg, 100mg of active substance
0.5 mg 3«a 25 mg 100 mg
‘ ctive nce
mg/per tablet mg/per tablet mg/per tablet mg/per tablet
et granulation
(D O:2<(D (I) C C" (I) ,_..(D 3 0CD 2.5000 5.000 25.00 100.00
Lactose
60.00 55.00 42.00 168.00
Monohydrate
Microcrystalline
.00 20.00 38.00 152.00
Hydroxypropy l
.00 5.00 7.50 30.00
Cellulose
Croscarmellose
4.00 4.00 24.00
Purified Water
Dry Adds
Microcrystalline
.00 30.00 120.00
Cellulose
Colloidal silicon
0.50 0.75 3.00
9-. o5. 0. CD
Magnesium stearate 0.50 0.50 0 75 3.00
100.00 100.00 600.00
The active nce, e.g. the compound (l.9), ably in the crystalline form (l.9X),
hydroxypropyl cellulose, and croscarmellose sodium are mixed in a blender. This premix is
mixed with lactose monohydrate and a portion of microcrystalline ose. The resulting
blend is granulated with purified water. Multiple granulation subparts may be produced for an
individual tablet batch, as needed, depending on the batch size and equipment used.
The granulation is discharged onto dryer trays and dried. The ation is then milled. The
remainder of the microcrystalline cellulose is added (as a premix with the colloidal silicon
dioxide for all strengths other than the 0.5 mg) to the milled granulation, and mixed. The
ium stearate is premixed with a portion of the blend, screened into the remainder of
the granulation, and mixed.
The final tablet blend is compressed into s using a tablet press. The finished tablets are
packaged using a suitable ner closure system.
Example 11: Tablets containing 1mg, 5mg, 25mg of active substance
1 mg 5 mg 25 mg
‘ ctive substance
mg/per tablet mg/per tablet mg/per tablet
et granulation
(D O:P.<(D (I) C C" (I) ,_..(D 3 0CD 1.00 5.00 25.00
Lactose
63.00 59.00 39.00
Monohydrate
Microcrystalline
.00 20.00 20.00
Cellulose
Hydroxypropy |
3.00 3.00 3.00
Cellulose
Croscarmellose
2.00 2.00 2.00
Purified Water
Dry Adds
Microcrystalline
.00 10.00 10.00
Cellulose
Colloidal silicon
0.50 0.50 0.50
9-. o5. 0. CD
Magnesium stearate 0.50 0.50 0.50
100.00 100.00 100.00
WO 07557 2012/062922
The active substance, e.g. the compound (l.9), preferably in the crystalline form (l.9X), is
passed through a screen and added to a blender or a high shear granulator. The
hydroxypropyl ose and croscarmellose sodium are passed h a screen, added to
the drug substance, and mixed. The intra-granular portion of microcrystalline cellulose is
passed through a screen into a high shear granulator and mixed with the drug substance
premix. Lactose is then added by passing the material through a screen into the granulator
and mixing. The resulting blend is granulated with purified water. For larger batches, multiple
granulation subparts may be produced for an individual tablet batch, as needed, depending
on the batch size and equipment used.
The granulation is discharged onto dryer trays and dried. The granulation is then passed
through a mill into a blender. The colloidal silicon dioxide is pre-mixed with a portion of the
extra-granular microcrystalline cellulose. This premix is passed through a mill into the
blender, followed by the remaining granular microcrystalline cellulose, and mixed with
the milled granulation. The magnesium te is premixed with a portion of the blend,
passed through a mill into the remainder of the granulation, and mixed.
The final tablet blend is compressed into tablets using a tablet press. The finished tablets are
packaged using a suitable container closure system.
es of Tests with regard to Properties of Pharmaceutical Compositions and
Pharmaceutical Dosage Forms
1. Disintegration Test
Disintegration test was med as described in USP31-NF26 82, chapter 701
(disintegration).
2. Dissolution Test
The standard dissolution test is described in USP31-NF26 82, r 711 (dissolution). The
paddle method (Apparatus 2) with an agitation speed of 50 rpm was used. The ution
media is 900 mL 0.05 M Potassium phosphate buffer pH 6.8 at a temperature of 37°C.
Samples are taken after 10, 15, 20, 30 and 45 minutes. The samples are analyzed via HPLC.
3. Particle Size Distribution Measurement by Laser Diffraction
Particle size distribution measurement is performed for example via light ring or laser
diffraction technique. To determine the particle size the powder is fed into a laser
WO 07557
diffraction spectrometer for example by means of a dispersing unit. The test method is
described below in detail:
Equipment: Laser Diffraction Spectrometer Sympatec HELOS Particle Sizer.
Lens: R31 (0.5/0.9um )
Sample Dispersing Unit: Dry disperser RODOS/M
Vacuum: Nilfisk
Feeder: ASPIROS
Feed ty: 60.00 mm/s
Primary re: 2.00 bar
Injector depression: maximize (mbar)2
Reference ement: 10 seconds
Cycle Time: 100 msec
Trigger Conditions: Start 0.0 seconds after optical concentration 2 1% valid always
Stop after 5.0 s optical concentration 5 1% or after 30 seconds real time
Optical Concentration: Approximately range 3 — 12 %
Evaluation: HRLD
Sample Size: imately 100 mg
Number of measuremtns: 2 (duplicate)
The instrument is set up according to the manufacturer's recommendation and using the
cturer provided software. The sample container is thoroughly mixed and tumbled prior
to removing a portion of the sample to ensure that a representative sample is tested.
Duplicate samples are prepared by using a spatula to transfer approximately 100 mg of a
sample into the ASPIROS glass vials and cap the vials. The capped cials are placed into the
4. Tablet hardness and friability
Tablet hardness and friability test was performed as described in USP31-NF26 82, chapter
1217 (tablet breaking force).
Example: ceutical composition of compound (l.9) and linagliptin
In the following an example of pharmaceutical compositions comprising the compound (l.9)
(API 1) and linagliptin (API 2) and their manufacture are provided. The active pharmaceutical
ingredients API 1 and API 2 are processed in one granulation step and a one-layer tablet is
pressed. At the beginning copovidone is dissolved in purified water at ambient temperature
(about 20°C) to produce a granulation liquid. API 1, API 2, ol, pregelatinized starch
and corn starch are blended in a suitable mixer, to e a pre-mix. The pre-mix is
moistened with the granulation liquid and subsequently granulated. The moist granulate is
sieved through a suitable sieve. The granulate is dried at about 60 °C inlet air temperature in
a fluid bed dryer until a loss on drying value of 1-4 % is obtained. The dried granulate is
sieved through a sieve with a mesh size of 1.0 mm.
Crospovidone and talc are added to the dried granulate and mixed for 5 minutes to produce
the main blend. Magnesium stearate is passed through a sieve for delumping and added to
main blend. Subsequently the final blend is produced by final blending in a suitable blender
for three minutes and compressed into 8 mm round tablet cores with a compression force of
16 kN.
Hydroxypropyl cellulose, polyethylene glycol, talc, titanium dioxide, mannitol and iron
oxide are suspended in purified water in a suitable mixer at ambient temperature to e
a coating sion. The tablet cores are coated with the coating suspension to a weight
gain of about 3 % to produce oated tablets. The following formulation variants can be
obtained:
3«I \ 3«a \ 3«3 \ mg/ 3«a \
Ingredient
ablet ablet ablet ablet ablet
‘ Pl 1 .5 9‘ o 10.0 ‘ 9‘o 0‘.0o
‘ Pl 2 9‘ o 9‘ o 9‘ o
ol 113.55 111.05 106.05 '1.05 0‘ 0‘ o 01
Pregelatinised starch 18.0 18.0 18.0 18.0 18.0
Maize starch 19.8 19.8 19.8 19.8 19.8
Crospovidone fl 9° on 9° 03 fl 9° on
Copovidone A 9‘ -l> 9‘ -l> ' 9‘ -l>
alc 0 0
Magnesium stearate 0.15 (JO .15 (JO .15 a I_\ O1 00 .15
Hydoxypropyl
1.7500 1.7500 1.7500 1.7500 1.7500
methylcellulose
hylene glycol 0.6000 0.6000 0.6000 0.6000 0.6000
lron oxides 0.0125 0.0125 0.0125 0.0125 0.0125
itanium dioxide 0.7375 0.7375 0.7375 0.7375 0.7375
WO 07557
Mannltol -1 0000- 1 0000 -
WE
Claims (10)
1. Use of the SGLT2 tor 1-chloro(β-D-glucopyranosyl)[4-((S)-tetrahydrofuran- 3-yloxy)-benzyl]-benzene for the manufacture of a medicament for preventing, slowing the progression of, delaying or treating renal iltrative injury in a patient in need thereof, wherein the patient has a glomerular tion rate (GFR) equal to or greater than 140mL/min/1.73 m2, wherein the medicament comprises 10 mg or 25 mg of the SGLT2 inhibitor, and wherein the patient is an individual sed or showing one or more of the ing conditions: (a) diabetes mellitus; (b) congenital or acquired obstructive uro/nephropathy; (c) progressive chronic kidney disease (CKD); (d) acute renal failure (ARF); (e) renal transplant recipients; (f) renal transplant donors; or (g) unilateral total or partial nephrectomized patients.
2. The use according to claim 1, wherein the t is an individual sed with or showing diabetes mellitus.
3. The use according to claim 1, wherein the patient is an individual diagnosed with or showing type 1 diabetes mellitus, type 2 diabetes mellitus, maturity onset diabetes of the youth (MODY), latent autoimmune diabetes of adults (LADA) or pre-diabetes.
4. The use according to claim 1, wherein the patient: (1) is an individual diagnosed of one or more of the ions selected from the group consisting of overweight, obesity, visceral obesity and abdominal obesity; or (2) is an individual who shows one, two or more of the following conditions: (a) a fasting blood glucose or serum e concentration greater than 100 mg/dL, in particular greater than 125 mg/dL; (b) a postprandial plasma glucose equal to or greater than 140 mg/dL; (c) an HbA1c value equal to or greater than 6.0 %, equal to or greater than 6.5%, or equal to or greater than 8.0 %; or AH26(10398701_1):RTK (3) is an individual wherein one, two, three or more of the following conditions are present: (a) obesity, visceral obesity and/or abdominal obesity, (b) triglyceride blood level ≥ 150 mg/dL, (c) olesterol blood level < 40 mg/dL in female patients and < 50 mg/dL in male patients, (d) a systolic blood pressure ≥ 130 mm Hg and a lic blood pressure ≥ 85 mm (e) a fasting blood glucose level ≥ 100 mg/dL; or (4) is an individual with morbid obesity.
5. The use according to any one of claims 1 to 4, wherein the medicament additionally comprises one or more pharmaceutically acceptable carriers.
6. Use of the SGLT2 inhibitor 1-chloro(β-D-glucopyranosyl)[4-((S)-tetrahydrofuran- 3-yloxy)-benzyl]-benzene for the manufacture of a medicament for preventing, slowing the progression of, delaying or treating a condition or disorder selected from the group consisting of hyperfiltrative diabetic nephropathy, renal hyperfiltration, glomerular iltration, renal allograft hyperfiltration, satory hyperfiltration, hyperfiltrative chronic kidney disease, hyperfiltrative acute renal e and compensatory hyperfiltration, wherein the compensatory hyperfiltration is in association with obstructive uro/nephropathy or morbid obesity, in a patient in need thereof, wherein the t has a GFR equal to or r than 140 mL/min/1.73 m2, wherein the medicament comprises 10 mg or 25 mg of the SGLT2 inhibitor, and wherein the patient is an individual diagnosed or showing one or more of the ing conditions: (a) diabetes mellitus; (b) congenital or acquired obstructive uro/nephropathy; (c) progressive chronic kidney e (CKD); (d) acute renal failure (ARF); (e) renal transplant recipients; (f) renal transplant donors; or (g) unilateral total or partial nephrectomized ts.
7. The use according to claim 6, wherein the patient is an individual diagnosed with or showing diabetes mellitus. AH26(10877199_1):JJC
8. The use according to claim 6, wherein the patient is an individual diagnosed with or showing type 1 diabetes mellitus, type 2 diabetes mellitus, maturity onset diabetes of the youth (MODY), latent autoimmune es of adults (LADA) or pre-diabetes.
9. The use according to claim 6, wherein the t: (1) is an individual diagnosed of one or more of the conditions selected from the group consisting of overweight, y, visceral obesity and abdominal obesity; or (2) is an individual who shows one, two or more of the ing conditions: (a) a fasting blood glucose or serum glucose tration greater than 100 mg/dL, in particular greater than 125 mg/dL; (b) a postprandial plasma glucose equal to or greater than 140 mg/dL; (c) an HbA1c value equal to or r than 6.0 %, equal to or greater than 6.5%, or equal to or greater than 8.0 %; or (3) is an individual wherein one, two, three or more of the following conditions are present: (a) obesity, visceral obesity and/or abdominal obesity, (b) triglyceride blood level ≥ 150 mg/dL, (c) olesterol blood level < 40 mg/dL in female patients and < 50 mg/dL in male patients, (d) a systolic blood pressure ≥ 130 mm Hg and a diastolic blood pressure ≥ 85 mm (e) a fasting blood glucose level ≥ 100 mg/dL; or (4) is an individual with morbid obesity.
10. The use according to any one of claims 6 to 9, wherein the medicament additionally comprises one or more pharmaceutically able carriers. Boehringer Ingelheim International GmbH By the Attorneys for the Applicant SPRUSON & FERGUSON Per: AH26(10398701_1):RTK
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161505598P | 2011-07-08 | 2011-07-08 | |
US61/505,598 | 2011-07-08 | ||
PCT/EP2012/062922 WO2013007557A1 (en) | 2011-07-08 | 2012-07-03 | Pharmaceutical composition, methods for treating and uses thereof |
Publications (2)
Publication Number | Publication Date |
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NZ618546A NZ618546A (en) | 2016-02-26 |
NZ618546B2 true NZ618546B2 (en) | 2016-05-27 |
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