AU9825098A - Intravenous alendronate formulations - Google Patents

Description

S F Ref: 365900DI

AUSTRA!JA

PATENTS ACT 1990 FOR A STANDARD PATENT Name and Address of Applicant: Actual Inventor(s): Address for Service: Invention Title: Merck Co., Inc.

126 East Lincoln Avenue Rahway New Jersey 07065 UNITED STATES OF AMERICA Gerald S Brenner.. *Musa M Ghannaln Spruson Ferguson, Patent Attorneys Level 33 St Martins Tower, 31 Market Street Sydney, New South Wales, 2000, Australia Intravenous Alendronate Formulations The following statement Is a full descriptionh of this invention, Including the best method of performing it known to me/rjS:-

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-1- TITLE OF THE INVENTION INTRAVENOUS ALENDRONATE FORMULATIONS FIELD OF THE INVENTION The instant invention relates to the use of isotonic intravenous formulations of alendronate, 4-amino-l-hydroxybutylidene-1,l-bisphosphonic acid monosodium trihydrate, for the treatment of metastatic bone disease, hypercalcemia of malignancy, and/or metabolic bone disease including osteoporosis and Paget's disease in human patients.

BACKGROUND OF THE INVENTION Metastatic bone disease involves tumor-induced skeletal metastases which commonly result from breast cancer, prostate cancer.

15 lung cancer, renal cancer, thyroid cancer and multiple myeloma. The prevalence of bone metastases in patients with these cancers may be as high as 60-85%. Patients with these diseases that have bone dominant or bone only metastases frequently have prolonged survival, usually associated with clinical morbidity. The most frequent clinical manifestations of bone metastases are pain; pathological fracture, mmobility, nerve root or spinal cord compression, hypercalcemia and compromised hematopoiesis. The scope of metastatic bone disease is Shighlighted by the fact that on any given day, approximately 4 million people worldwide suffer from cancer pain and that at least 40-50% of all cancer pain is duC to skeletal metastases.

Hypercalcemia of malignancy is also tumor-induced. It is characterized by high levels of serum calcium and is often associated with metastatic bone disease, particularly with non-ambulatory patients.

It is estimated that hypercalcemia develops in 5% to 10% of hospital cancer patients. Symptoms of hypercalcemia include fatigue, malaise, anorexia, polydipsia, nausea, constipation, muscle weakness, apathy, obtundation and even coma. These metabolic complications of t 1 i s -2malignancy mostly reflect a disseminated disease. Thus, in the majority of cases, malignancy is recognized before the appearance of hypercalcemia. However, in rare situations, such as neuroendocrine tumors, hypeicalcemia may run a slowly developing course and even precede the discovery of the tumor.

The category of metabolic bone disease includes osteoporosis and Paget's disease, in which .steoporosis is one of the most important disorders associated with aging. More than 1.5 million Americans have fractu±rs related to osteoporosis each year, with i 10 attendant pain, deformiry and loss of independence. The annual cost to the U.S. health care system i. at least $10 billion. Because of the aging of the population and increase.< over time in the incidence of fractures.

these already huge costs will inre than double over the next 30 years Sunless a comprehensive program of prevention and treatment is initiated 15 soon. The most important preventable cause of fractures is low bone Smass. During the course of their lifetimes, women lose about percent of their cancellous bone and 30 percent of their corical bone, and men lose about 30 percent and 20 percent, respectively. Cancellous 0. bone is concentrated in the spinal column and at the ends of long bones; these areas are the main sites of osteoporotic fractures. The tendency of the elderly to fall, however, is an important independent cause of fractures. Although little can be done at present to prevent such falls, important advances have been made in methods of retarding bone loss involving the use of bisphosphonates.

25 Alendronate, 4-amino-l-hydroxvbutylidene-1,1bisphosphonic acid monosodium trihydrate, is a new bisphosphonate i agent for combatting bone resorption in metabolic bone diseases including osteoporosis and Paget's disease and is described as a composition, method of use and synthesis along with other pharmaceutically acceptable salts in U.S. Patents 4,922,007 and 5,019.651 (both assigned to Merck).

-3- Alendronate is also used in treating metastatic bone disease for example, as described in Cancer 72, (Supplement) 3443-3452(1993) by S.D. Averbuch. Its use in treatir- hypercalcemia of malignancy is described in Journal of Clinical Oncology, Vol. 11, No 8 (August), 1993, pp. 1618-1623 by S.R. Nussbaum et al.

Alendronate currently is administered orally or intravenously to patients. The advantage of intravenous therapy over oral dosage therapy is that therapeutically higher levels of serum alendronate can be achieved in a relatively short time period. This is especially important in hypercalcemia of malignancy where it is desired to lower serum calcium levels as quickly as possible to minimize calcium deposition and resulting bone disorders.

However, a major problem is that intravenous solutions of alendronate are prepared and packaged in glass containers and tend to form a precipitate during shelf storage. This has shown to be a result of Smetal ion precipitation of alendronate at increasingly higher pH values forming insoluble metal complexes. Precipitates are very dangerous in an intravenous formulation since they can lead to embolisms and blocking of capillaries which can be fatal. Thus, intravenous formulations for clinical studies and marketing must pass a series of rigid government (United States or international) and compendial tests, including the USP (United States Pharmacopeia in the United States) test for particulate matter. With respect to packaging, the use of glass containers is highly desirable since the formulation contents can be S 25 quickly inspected for the presence of particulates, and glass is a very efficient and convenient medium for packaging.

What is desired is a therapeutically effective alendronate intravenous formulation which is solution stable, isotonic with human blood, can be packaged in glass, meets government and compendial (USP in the US) particulate standards, and which can be used as effective therapy to optimally treat patients with metastatic bone disease, hypercalcemia of malignancy and/or metabolic bone disease.

n -4- SUMMARY OF THE INVENTION We have discovered that a sodium citrate/citric acid buffer can maintain the pH of the alendronate intravenous formulation between 4-8 and acts as a complexing agent to maintain metal ions in solution which are leached out of the glass container. Both of these effects, maintaining the lower pH and complexing metal ions by the citrate buffer, prevents metal ions from precipitating alendronate and can maintain the intravenous formulation in an acceptable particulate profile for storage and subsequent use.

By this invention there is provided a pharmaceutical composition comprising a pharmaceutically effective amount of alendronate, in a pharmaceutically acceptable aqueous carrier for intravenous application and a sufficient amount of a buffer to maintain the pH of the composition in the range of 4 to 8 to prevent the 15 precipitation of alendronate by metal ions in aqueous solution, said composition being isotonic with human blood.

The present invention also provides a method for treating and/or preventing metastatic bone disease, hypercalcemia of malignancy and/or metabolic bone disease in a subject who is in need of same comprising the step of administering to said patient a pharmaceutically effective amount of alendronate, in a stable citrate-buffered, isolo;ic.

intravenous formulation.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS Liquid intravenous solutions of alendronate offer the advantages of ease of administration, increased compliance for ambulatory patients, who have difficulty ingesting solid oral dosage forms, and for hospitalized patients who require therapeutically large doses of alendronate in a short time period.

This method is especially useful for treating metastatic bone disease and hypercalcemia and can also be used for treating patients to J inhibit bone resorption in other metabolic bone disorders, Paget's disease and osteoporosis.

The term "inhibition of bone resorption" as used herein, refers to treatment and prevention of bone loss, especially inhibiting the removal of existing bone either from the mineral phase ant/or the organic matrix phase, through direct or indirect alteration of osteoclast formation or activity. Thus, the term "inhibitor of bone resorption" as used herein refers to agents that prevent bone loss by the direct or indirect alteration of osteoclast formation or activity and which may increase bone mass in patient treatment populations.

The term "osteogenically effective" as used herein, means that amount which effects the turnover of mature bone. As used herein.

an osteogenically effective dose is also "pharmaceutically effective." The term "treatment" or "treating" as used herein shall mean providing a subject with an amount of alendronate sufficient to act prophylactically to prevent the development of a weakened and/or unhealthy state; and/or providing a subject with a sufficient amount of alendronate so as to alleviate or eliminate a disease state and/or the symptoms of a disease state, and a weakened and/or unhealthy state.

20 Pharmaceutical intravenous formulations of the invention will generally include an osteogenically effective amount of alendronate to treat mctastatic bone disease and/or hypercalcemia of malignancy and also to inhibit bone resorption, in addition to a pharmaceutically acceptable excipient. The compositions are advantageously prepared 25 together with liquid inert carriers, a useful one being water. Suitable liquid excipients/carriers are Water for Injection (USP in the US) and saline solution.

Other suitable excipients and other accessory additives are as follows: -6- -Solvents ethanol glycerol propylene glycol Stabilizers EDTA (ethylene diamine tetraacetic acid) citric acid Antimicrobial Preservative'S beuzyl alcohol methyl paraben propyl parabern Buffering Agenis citric acid/sodium. citrate potassium hydrogen tartrate so-dium hydrogen tartrate.

acetic acid/sodium acetate maleic acid/sodiuni maleate sodium hydrogen phthalate.

phosphoric acidipotassium dihydrogen phosphate phosphoric acidldisodium hydrogen phosphate Tonicity ModifirrS sodium chloride mannitol dextrose -7- Alendronate is present in an amnount of about 0.5 to Cllgrxn/iiiter of the composition and a useful value is 2-5 mig/rn i of composition.

In addition, the presence of a buffer is necessary to maintain the aqueous p1- in the ranve of 4-8 and a useful range being 4-6.

The buffer svstem is generallv a mixture of a weak acid and a soluble salt thereof, sodium citrate/citric acid; or the monocation or dication salt of a dibasic acid, potassium hy'drogen tartrate; sodium hydrogen tartrate, phosphoric acid/potassiurn dihydrogen phosphate. and phosphoric acid/dksodium hydrogen phosphate.

The amnount of buffr- system used is dependent on (I1) the desired pH; and the amount of alendronate. Generally, the amount I of buffer used is in a 0.5:1 to 50:1 mole ratio of buffer: alendronate (where the moles of buffer are taken as the combined moles of the buffer ingredients, sodium citrate and citric acid) of formulation !o) maintain a pH in the range of 4 tog8 and generally, a 1: 1 to 10: 1 mole ratio of buffer (combined) to alendronate. present is used.

A useful buffer in the invention is sodium citrate/citric acid in the range of 5 to 50 mg per ml. sodium citrate to I to 15 mug per ml.

citric acid, sufficient to maintain an aqueous pH of 4-6 of ihe composition, The buffer agent Is also present to prevent the precipitation ofalendronate through soluble metal complex formation with dissolved metal ions, Ca, MNg, Fe, Al, Ba, which may leach out of glass containers or rubber stoppers or be present in ordinary tap water. Tht agent acts as a competitive complexing agent with the alendronate and produces a soluble metal complex whereas alendronate generally forms an insoluble metal complex leading to the presence of undesirable particulate-S.

In addition, the presence of an agent, sodium chloride in an amount of about of 1-8 mg~ml, to adjust the tonicity to the same value of human blood is required to avoid the swelling or shrinkageo erythrocytes upon administraion of tlie intravenous formulation leadinea to undesirable side effects such as nausea or diarrhea and possibly to associated blood disorders. In iPeneral, the tonicity of the formulation matches that of human blood which is in the range of 28R2 to 299.

mOsmlkg. and in general is 285 rnOsrn/g, which is equivalent to the osmotic pressure corresponding to a 0-9 solution of sodium chloride.

The precise dosage by intravenous therapy necessary will vary with the age, size, sex and conidition, of the subject, the nature and severity of the disorder to be treated, and the like; thus, a precise effective amount cannot be specified in advance and will b~e determined 15 by the caregiver. However, appropriate amonis may be determined by routine experimentation with well-Known animal models. In general terms, an effective dose for alendronate in an intravenous liquid formulation is about 1-5 to 3000 mg/kg of body weighi and a useful range is, about 10 meg/kg to r-bout 200 mgAkg of body weight. A dosage of 2.5-10 mg per person per day introduced over a 2-10 -hour period is 4 20 a useful intravenous dosage regimen.

The intravenous formnuiation of alendronate c-an be administered by direct intravenous injecton, i-v. bolus. or can be administered by infusion by addition to an appropriate infusion solutioll such as 0.9% sodium chloride injection or other compatible infusion 25 solution.

An example of an intravenous dosage fo m of alendronate is as follows, General Formulation Alendronate 0.5 10.0 rug Sodium Citrate 5 -50 m Citric Acid Sodium Chloride 1 SMP Water for Injection (USP) q-s. I nil- *Additional agents such as cosolvents, preser Valves.

stabilizers and buffering agents mayi also be specifically incorpor-ated ill the formulation.

The followig example is representative of the invention av contemplated by the inventors and should not be construed as heing a limitation on the scope or spirit of the invention as claimed.

EXAMPLE

Specific Formulatior Alendronate 3.33 mug (equivalent to 2-5 rat, of the acid) Sodium Chloride USP Reagent Crystals 4.91 Mu Sodium Citrate USP 10.3 mug Citric Acid USP 2-R9 mg Water for Injection (USP) q.s. I mL Method of Manufacture Utilizing the above quantities, alendronate is dissolved at room temperature In a previously prepared solution of sodium chloride.

citric acid, and sodium citrate in Water for Injection (USP. see page 1636 of the below reference cite))- The resulti solution is filtered in a sterile environment through a 0.22 micron filter and subdivided into Type I glzoss vials.

each with a stopper and alurninum, sea].

The vials (contents) arz then individually lested accordinge to the applicable govemrnt and compendial standards for i sterile intravenous solutions. As an example for markeing in the US. the Vials would be tested via following Protocols found in the US Pharnicopela.

See United States Pharmacopcial/National Formulary. for 11495, pulihe b.UidSttsParmacopcial Convention, Inc., Rockville.

Marvland, copyrgh 1994. "Gencral Te.-ts and AssaN.N". pages M48 to Sterility: LISP method.(page 16%R of above reence cite) Pvrogen:- USP method (page 171IF of above reference cite) Particulates: LISP method (paee 19 13-' of aboKve reference cite).

Tonicity: LISP method (pape 18 13 of above reference USP method (page 18919 of above reference cite) CONIPARATIVE EXAMIPLE a hw b similar folato as shw bve, in the same proportions but based on O-Imr-ml of alendronate. mnd Jacking, so:dium citrate and citric acid, form-- a pre-cipitate after staniding for one year at 30 degrct Centigrade.

Claims (14)

1. 2. The pharmaceutical composition of claim 1, wherein said alendronate is present in the amount of 0.5 to 10 milligrams per milliliter of composition.
2. 3. The pharmaceutical composition of clain 1, wherein said pharmaceutically acceptable excipient is water.
3. 4. A method for treating a condition selected from the group consisting of hypercalcemia of malignancy, metastatic bone disease and metabolic bone disease in a human patient in need of such treatment, the method comprising the step of administering to said patient a pharmaceutically effective dose of the intravenous alendronate pharmaceutical composition as defined in any of claims I to 3. 15 5. An intravenous alendronate pharmaceutical composition as defined in any one of claims 1 to 3 when used for treating a condition selected from the group consisting of hypercalcemia of malignancy, metastatic bone disease and metabolic bone disease.
4. 6. Use of an alendronate pharmaceutical composition in the manufacture of a medicament for treating a condition selected from the group consisting of hypercalcemia of malignancy, metastic bone disease and metabolic bone disease.
5. 7. A pharmaceutical composition comprising a pharmaceutically effective amount of alendronate, in a pharmaceutically acceptable aqueous carrier for intravenous application and a sufficient amount of a buffer to maintain the pH of the composition in the range of 4 to 8, said composition being isotonic with human blood and wherein the 25 buffer is selected from the group consisting of citric acid/sodium citrate; potassium hydrogen tartrate; sodium hydrogen tartrate; acetic acid/sodium acetate; maleic acid/sodium maleate; sodium hydrogen phthalate; phosphoric acid/potassium dihydrogen phosphate and phosphoric acid/disodium hydrogen phosphate.
6. 8. The pharmaceutical composition of claim 7, wherein said buffer s selected from the group consisting of sodium citrate/citric acid, potassium hydrogen tartrate, sodium hydrogen tartrate, phosphoric acid/potassium dihydrogen phosphate, and phosphoric acid/disodium hydrogen phosphate.
7. 9. The pharmaceutical composition of claim 8, wherein said buffer is sodium citrate/citric acid.
8. 10. The pharmaceutical composition of any one of the preceding claims, wherein said alendronate is present in the amount of 0.5 to 10 milligrams per milliliter of i composition. S1. The pharmaceutical composition of any one of the preceding claims, wherein said pharmaceutically acceptable carrier is water. I.; A 1 12
9. 12. The pharmaceutical composition of any one of the preceding claims, wherein said buffer is present in an amount of 0.5 to 50 to 1 mole ratio of buffer:alendronate.
10. 13. The pharmaceutical composition of any one of the preceding claims, wherein said pH is in the range of 4 to 6. s 14. The pharmaceutical composition of any one of the preceding claims being an aqueous solution of the following formula: Alendronate 0.5 10.0mg Sodium Citrate 5 Citric Acid 1 Sodium Chloride 1 8mg Water for Injection q.s. ImL The pharmaceutical composition of claim 8 having the formula: Alendronate 3.33mg Sodium Citrate 4.91mg 15 Citric Acid 10.29mg Sodium Chloride 2.88mg S. 6 Water for Injection q.s. ImL
11. 16. A pharmaceutical composition comprising a pharmaceutically effective amount of alendronate, substantially as hereinbefore described with reference to any one of the examples but excluding the comparative examples.
12. 17. A method for treating a condition selected from the group consisting of hypercalcemia of malignancy, metastatic bone disease and metabolic bone disease in a human patient in need of such treatment, the method comprising the step of administering to said patient a pharmaceutically effective dose of the intravenous alendronate 25 pharmaceutical composition as defined in any one of claims 7 to 16.
13. 18. An intravenous alendronate pharmaceutical composition as defined in any one of claims 7 to 16 when used for treating a condition selected from the group consisting of hypercalcemia of malignancy, metastatic bone disease and metabolic bone disease.
14. 19. The use of alendronate for the manufacture of an intravenous medicament for 3o treating a condition selected from the group consisting of hypercalcemia of malignancy, metastatic bone disease and metabolic bone disease. Dated 22 December, 1998 Merck Co., Inc. Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON