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Tiludronic acid | CAS No: 89987-06-4 | GMP-certified suppliers
A medication that treats Paget’s disease of bone by reducing abnormal bone remodeling and lowering elevated serum alkaline phosphatase in symptomatic patients or those at risk of complications.
Therapeutic categories
Primary indications
- Tiludronic acid is indicated to treat Paget's disease of bone in patients with serum alkaline phosphatase levels ≥2 times the upper limit of normal, with symptoms, or with risk of future complications
Product Snapshot
- Tiludronic acid is an oral small molecule available in tablet formulation
- It is primarily indicated for the treatment of Paget's disease of bone
- The product is approved for use in the US market with both human and veterinary approvals
Clinical Overview
Pharmacodynamically, tiludronic acid acts by inhibiting osteoclastic bone resorption. Bisphosphonates, including tiludronic acid, localize to the bone matrix through strong binding to hydroxyapatite. During bone resorption, osteoclast-mediated acidification releases the bisphosphonate, allowing cellular uptake via fluid-phase endocytosis. Within osteoclasts, tiludronic acid inhibits protein-tyrosine-phosphatase activity, elevating tyrosine phosphorylation levels and disrupting the formation of podosomes, which are F-actin ring structures essential for osteoclast attachment to bone. Additionally, tiludronic acid inhibits vacuolar-type H+-ATPases, further impairing podosome assembly and osteoclast function, thereby preventing bone resorption.
The drug exhibits a prolonged duration of action due to its slow clearance from bone tissue and a wide therapeutic window. Absorption and distribution characteristics reflect its high affinity for bone, with primary elimination via the renal route. Safety considerations include the potential for upper gastrointestinal mucosal irritation and a risk of gastric or duodenal ulcers, warranting patient counseling.
Tiludronic acid is classified among bisphosphonates and bone density conservation agents and is used primarily in the context of bone diseases characterized by excessive and disorganized bone remodeling. When sourcing tiludronic acid as an active pharmaceutical ingredient, attention should be paid to stringent quality control to ensure purity, polymorphic consistency, and compliance with international pharmacopeial standards to guarantee batch-to-batch reproducibility and safety.
Identification & chemistry
| Generic name | Tiludronic acid |
|---|---|
| Molecule type | Small molecule |
| CAS | 89987-06-4 |
| UNII | 6PNS59HP4Y |
| DrugBank ID | DB01133 |
Pharmacology
| Summary | Tiludronic acid is a bisphosphonate that binds to hydroxyapatite in bone and inhibits osteoclast-mediated bone resorption. It disrupts osteoclast podosome formation by inhibiting protein-tyrosine phosphatases and vacuolar ATPase activity, leading to osteoclast detachment from bone surfaces. These actions result in reduced bone turnover with prolonged duration due to slow skeletal clearance. |
|---|---|
| Mechanism of action | Bisphosphonates are taken into the bone where they bind to hydroxyapatite. Bone resorption by osteoclasts causes local acidification, releasing the bisphosphonate, which is taken into the osteoclast by fluid-phase endocytosis. Endocytic vesicles become acidified, releasing bisphosphonates into the cytosol of osteoclasts where they act. Osteoclasts mediate resorption of bone. When osteoclasts bind to bone they form podosomes, ring structures of F-actin. Tiludronate inhibits protein-tyrosine-phosphatase, which increases tyrosine phosphorylation, and disrupts podosome formation. Tiludronic acid also inhibits V-ATPases in the osteoclast, though the exact subunits are unknown, preventing F-actin from forming podosomes. Disruption of the podosomes causes osteoclasts to detach from bones, preventing bone resorption. |
| Pharmacodynamics | Tiludronic acid is a bisphosphonate that prevents osteoclasts from resorbing bone. The duration of action is quite long due to the slow clearance from the bone, and the therapeutic window is wide. Patients should be counselled regarding the risk of upper GI mucosal irritation as well as gastric and duodenal ulcers. |
Targets
| Target | Organism | Actions |
|---|---|---|
| Hydroxylapatite | Humans | antagonist, binder |
| Adenosine triphosphate (ATP) | Humans | inhibitor |
| Tyrosine-protein phosphatase non-receptor type 12 | Humans | inhibitor |
ADME / PK
| Absorption | A single 400mg dose of tiludronic acid reaches a C<sub>max</sub> of 3.35±1.07mg/L, with a T<sub>max</sub> of 1.7—0.9h, and and AUC of 27.2±9.0mg\*h/L. Tiludronic acid has an oral bioavailability of 2-11% with an average of 6%. |
|---|---|
| Half-life | The mean plasma elimination half-life is 150 hours, though the elimination rate from bone is unknown. The terminal phase half life is approximately 40h after a single IV dose of 10-30mg. |
| Protein binding | Tiludronic acid is approximately 90% protein bound in serum. It is mostly bound to albumin. |
| Metabolism | Tiludronic acid is not metabolized _in vitro_ in human liver microsomes. |
| Route of elimination | Tiludronic acid is 60% eliminated in the urine as the unchanged parent drug. |
| Volume of distribution | The volume of distribution of tiludronic acid is estimated to be between 30L and 60L. Due to the unknown clearance rate from bone, this may underestimate the true volume of distribution. |
| Clearance | Tiludronic acid has a renal clearance of 0.68L/h in healthy subjects and 0.47L/h in subjects with Paget's disease. Approximately 50% of tilurdronic acid binds to bone but the rate of clearance from the bone is unknown. |
Formulation & handling
- Tiludronic acid is a small molecule bisphosphonate intended for oral administration in tablet form.
- Administer on an empty stomach, at least 2 hours before or after food, calcium supplements, or antacids to avoid reduced bioavailability.
- Ensure dosing with a full glass of water to facilitate absorption and minimize mucosal irritation.
Regulatory status
| Lifecycle | The active pharmaceutical ingredient's primary patents expired between 2010 and 2011, indicating established market presence in the United States. Following patent expiration, generic versions may be available, reflecting a mature lifecycle stage in this market. |
|---|
| Markets | US |
|---|
Supply Chain
| Supply chain summary | Tiludronic acid is supplied primarily by originator companies with branded products such as Skelid marketed in the US. The presence of patents expiring around 2010–2011 in the US and Canada indicates that the product is likely subject to existing or forthcoming generic competition. The supply chain is focused on North American markets, with limited information on presence in EU or other regions. |
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Safety
| Toxicity | Patients experiencing an overdose may present with hypocalcemia. Patients given doses of 6mg/kg/day for 2 days have experienced acute renal failure and death. Treat overdose with symptomatic and supportive care. Dialysis will not be useful for removal of the drug from serum. |
|---|
- Overdose may cause hypocalcemia and acute renal failure
- Fatalities have been reported at doses of 6 mg/kg/day for 2 days
- Dialysis is ineffective for serum drug removal in overdose situations
Tiludronate is a type of Means for diseases of the bone and muscular system
The pharmaceutical API subcategory known as "Means for diseases of the bone and muscular system" refers to a specialized class of active pharmaceutical ingredients (APIs) designed to target and treat various disorders related to the skeletal and muscular systems. These APIs play a crucial role in the development of medications that alleviate symptoms and improve the quality of life for individuals affected by bone and muscular conditions.
One common group of APIs in this subcategory includes bisphosphonates, which are widely used for the treatment of osteoporosis. These compounds inhibit bone resorption, thereby increasing bone density and reducing the risk of fractures. Bisphosphonates act by targeting specific enzymes involved in bone breakdown, preventing excessive bone loss.
Another significant class of APIs for bone and muscular diseases are muscle relaxants. These compounds help alleviate muscle spasms and stiffness associated with conditions such as muscle strains, sprains, and certain neurological disorders. Muscle relaxants work by interfering with the signals sent between the brain and the muscles, inducing relaxation and reducing pain.
Additionally, APIs like calcitonin analogs are utilized for the management of conditions such as Paget's disease and osteoporosis. Calcitonin analogs function by inhibiting osteoclast activity, reducing bone resorption, and promoting bone formation.
In summary, the subcategory of "Means for diseases of the bone and muscular system" encompasses APIs that target bone metabolism, muscle relaxation, and bone remodeling processes. These pharmaceutical ingredients play a vital role in the development of medications aimed at improving the well-being and mobility of individuals suffering from bone and muscular disorders.
Tiludronate (Means for diseases of the bone and muscular system), classified under Metabolic Bone Disease Agents
Metabolic Bone Disease Agents are a category of pharmaceutical active pharmaceutical ingredients (APIs) that are specifically designed to treat and manage conditions related to the bones and their metabolism. These agents play a crucial role in the treatment of various metabolic bone diseases, including osteoporosis, Paget's disease, and rickets.
The primary function of Metabolic Bone Disease Agents is to regulate bone remodeling and maintain bone health. They achieve this by targeting specific pathways involved in bone metabolism, such as osteoclast and osteoblast activity, calcium regulation, and vitamin D metabolism.
These APIs are commonly used in the development of medications, including oral tablets, injectables, and topical formulations, for the effective treatment of metabolic bone diseases. They are carefully formulated to optimize their pharmacokinetic and pharmacodynamic properties, ensuring maximum efficacy and minimal side effects.
Metabolic Bone Disease Agents encompass a range of substances, including bisphosphonates, selective estrogen receptor modulators (SERMs), calcitonin, and vitamin D analogs. These APIs act through different mechanisms to address specific aspects of bone health, such as inhibiting bone resorption, promoting bone formation, or regulating calcium levels.
In conclusion, Metabolic Bone Disease Agents are a vital category of pharmaceutical APIs used in the development of medications for the treatment and management of various metabolic bone diseases. These agents target specific pathways involved in bone metabolism to regulate bone remodeling, enhance bone health, and alleviate the symptoms associated with these conditions.
Tiludronate API manufacturers & distributors
Compare qualified Tiludronate API suppliers worldwide. We currently have 1 companies offering Tiludronate API, with manufacturing taking place in 1 different countries. Use the table below to review supplier type, countries of origin, certifications, product portfolio and GMP audit availability.
| Supplier | Type | Country | Product origin | Certifications | Portfolio |
|---|---|---|---|---|---|
| Sanofi | Producer | France | Unknown | CoA, USDMF | 93 products |
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