Sina Doxosome / سینا دوکسوزوم

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SinaDoxosome®

(Doxorubicin HCl Liposome Injection 2 mg/ml)

Encapsulated Drugs In Liposome

What Are Liposomes?

Liposomes are colloidal, spherical microscopic vesicles consisting one or more self-assembled lipid bilayers enclosing a similar number of aqueous compartments. They are usually classified on the basis of their size and the number of bilayers: multilamellar vesicles (MLV, 0.2-20 mM), large unilamellar vesicles (LUV, 100-500 nm) and small unilamellar vesicles (SUV, 25-100 nm).

Since their discovery by Bangham at 1965, they became very versatile tools in biology, biochemistry and medicine. Liposomes are used as drug delivery vehicles to increase the efficacy and specificity of drugs. Liposomes, because of their amphiphilic nature, can serve as carriers for water soluble as well as lipid soluble drugs. Lipid soluble drugs can be introduced into the lipid bilayer, and water soluble drugs can be encapsulated into the aqueous compartment of liposomes. Liposomes are also extensively used for the delivery of peptides, proteins, vaccines, and therapeutic oligonucleotides.

The main constituent of liposomes is phospholipids. Cholesterol is often included in the liposome formulation. Cholesterol, because of its rigid steroid ring system which interferes with the motion of fatty acid tails, stabilizes the lipid bilayer and decreases the leakage of encapsulated drug.

One of the main drawbacks of conventional liposomes -made of phospholipids and cholesterol- after intravenous injection is their rapid clearance from the blood by the phagocytic cells of RES(Reticuloendo thelial System). Altering the liposome surface by adding hydrophilic substituents, such as polyethylene glycol derivatives (PEG-Liposomes), reduces RES uptake and prolongs the circulation of the liposomes in the blood.

The nano size is important for the liposomal products to enable long circulation time and to allow for tumor penetration for the treatment of cancer by “Enhanced Penetration and Retention” mechanism.

 

  What are the advantages of using liposomes in drug delivery?

• Protect the encapsulated drug from metabolic degradation

• Solubilize the lipophilic drugs

• Increase the half-life of drug

• Could be used as sustained release vehicles

• It is possible to target them to selected tissues or cell

• Reduce the systemic toxicity of drugs

• liposomes are Biodegradable and biocompatible

 

 

SinaDoxosome®

(Doxorubicin HCl Liposome Injection 2 mg/ml)

Doxorubicin HCl is a drug used in cancer chemotherapy. Doxorubicin is commonly used in the treatment of a wide range of cancers, including hematological malignancies, many types of carcinoma, and soft tissue sarcomas. Doxorubicin’s most serious adverse effect is life-threatening heart damage, which limits its application. Therefore, various efforts have been made to reduce its side effects, including encapsulating it in nanoparticle systems such as nanoliposomes. The nano-liposomal form of doxorubicin HCl (Doxil®/Caelyx®) has entered the global market during the past few years by the approval of FDA.

The formulation and physicochemical properties of SinaDoxosome® is exactly equivalent to the foreign-made product (Doxil®/ Caelyx®). Particle size and zeta potential determination using Dynamic Light Scattering Instrument (Nano-ZS; Malvern, UK), extensive release studies in different media (at different pH and temperature)  and plasma,  biodistribution studies in mice bearing C26 colon carcinoma and bioequivalency studies in 9 volunteer patients show that there is no significant difference between SinaDoxosome® and Caelyx®.(fig 1-3)

SinaDoxosome® has been developed in the knowledge-based company of Exir Nano Sina with the support of Iran Nanotechnology Initiative Council. The product is produced in the site of Sobhan Oncology Pharmaceutical Co, Rasht, Iran.

 

 

Unique features of SinaDoxosome® are as follow:

1. The polyethylene glycol coating (stealth polymer) reduces the uptake of liposomes by RES cells, therefore increasing the life span of liposome in the blood (half-life about 53 hours).

2. The particle diameter of approximately 100 nm enables the nanoparticles to target the tumor tissues by enhanced permeation and retention mechanism.

3. The lipid matrix with high phase transition temperature and low permeability provides stable encapsulation of the doxorubicin in nanoliposomes and the internal aqueous buffer phase provides high loading efficiency for the Doxorubicin.

Advantages

■ Slow Release: reduced peak levels of free drug and prolonged tumor exposure

■ Change in Biodistribution: avoiding drug deposition in certain tissues will reduce tissue-specific toxicities

■ Tumor Targeting: passive accumulation by enhanced permeability and retention (EPR) effect

■ Effectively reduce the side effects of drugs

 Pharmacodynamic Properties

The active ingredient of SinaDoxosome® is doxorubicin HCl, a cytotoxic anthracycline antibiotic. The exact mechanism of the antitumour activity of doxorubicin is not known. It is generally believed that inhibition of DNA, RNA and protein synthesis is responsible for the majority of the cytotoxic effect. This is probably the result of intercalation of the anthracycline between adjacent base pairs of the DNA double helix, thus preventing their unwinding for replication.

 Pharmacokinetic Properties

 SinaDoxosome® is a long-circulating pegylated liposomal formulation of doxorubicin HCl that provides greater concentration of doxorubicin. Pegylated liposomes contain surface-grafted segments of the hydrophilic polymer methoxypolyethylene glycol (MPEG). These linear MPEG groups extend from the liposome surface creating a protective coating that reduces interactions between the lipid bilayer membrane and the plasma components. This allows the SinaDoxosome® liposomes to circulate for prolonged periods in the blood stream. Pegylated liposomes are small enough (average diameter of approximately 100 nm) to pass intact (extravasate) through defective blood vessels supplying tumours. Evidence of penetration of pegylated liposomes from blood vessels and their entry and accumulation in tumours has been seen in mice with C-26 colon carcinoma tumours. The pegylated liposomes also have a low permeability lipid matrix and internal aqueous buffer system that combine to keep doxorubicin HCl encapsulated during liposome residence time in circulation.

At equivalent doses, the plasma concentration and AUC values of SinaDoxosome® which represent mostly pegylated liposomal doxorubicin HCl (containing 95% to 100% of the measured doxorubicin) are significantly higher than those achieved with standard doxorubicin HCl preparations.

 

Indications

1) Breast Cancer:

SinaDoxosome® is indicated for the treatment of metastatic breast cancer, as monotherapy.

2) Ovarian Cancer:

SinaDoxosome® is indicated for the treatment of patients with ovarian cancer in women who have failed a first-line platinum-based chemotherapy regimen.

3) AIDS-Related Kaposi’s Sarcoma:

SinaDoxosome® is indicated for the treatment of AIDS-related Kaposi’s sarcoma in patients with low CD4 counts (<200 lymphocytes/mm3) and extensive mucocutaneous or visceral disease.

SinaDoxosome® may be used as first-line systemic chemotherapy, or as second line chemotherapy in AIDS-KS patients with disease that has progressed with, or in patients intolerant to, prior combination systemic chemotherapy comprising at least two of the following agents: a vinca alkaloid, bleomycin and doxorubicin (or other anthracyclines).

4) Multiple Myeloma:

SinaDoxosome® is also indicated, in combination with bortezomib, for the treatment of progressive multiple myeloma in patients who have received at least one prior therapy and who have already undergone or are unsuitable for bone marrow transplant.

Contraindications

SinaDoxosome® is contraindicated in patients who have a history of hypersensitivity reactions to its components or to doxorubicin HCl.

SinaDoxosome® should not be administered during pregnancy or while breast feeding.

SinaDoxosome® should not be used to treat AIDS-KS that may be effectively treated with local therapy or systemic alfa-interferon.

Dosage and administration

SinaDoxosome® should only be administered under the supervision of a qualified oncologist specialized in the administration of cytotoxic agents.

SinaDoxosome® exhibits unique pharmacokinetic properties and must not be used interchangeably with other formulations of doxorubicin HCl.

1-Breast Cancer / Ovarian Cancer

SinaDoxosome® is administered intravenously at a dose of 50 mg/m2 once every 4 weeks for as long as the disease does not progress and the patient continues to tolerate treatment.

For doses <90 mg: dilute SinaDoxosome® in 250 ml 5 % (50 mg/mL) glucose solution for infusion.

For doses >90 mg: dilute SinaDoxosome® in 500 ml 5 % (50 mg/mL) glucose solution for infusion. 19

To minimize the risk of infusion reactions, the initial dose is administered at a rate no greater than 1 mg/minute. If no infusion reaction is observed, subsequent SinaDoxosome® infusions may be administered over a 60-minute period.

In the breast cancer trial program, modification of the infusion was permitted for those patients experiencing an infusion reaction as follows:

5% of the total dose was infused slowly over the first 15 minutes. If tolerated without reaction, the infusion rate was doubled over the next 15 minutes. If tolerated, the infusion was completed over the next hour for a total infusion time of 90 minutes.

Subsequent SinaDoxosome® infusions may be administered over a 60 minute period.

 2-Multiple Myeloma

SinaDoxosome® is administered at 30 mg/m² on day 4 of the bortezomib 3 week regimen as a 1 hour infusion administered immediately after the bortezomib infusion. The bortezomib regimen consists of 1.3 mg/m² on days 1, 4, 8, and 11 every 3 weeks. The dose should be repeated as long as patients respond satisfactorily and tolerate treatment.

For doses < 90 mg: dilute SinaDoxosome® in 250 ml of 5 % (50 mg/ml) glucose solution for infusion.

For doses ≥ 90 mg: dilute SinaDoxosome® in 500 ml of 5 % (50 mg/ml) glucose solution for infusion.

The intravenous catheter and tubing should be flushed with 5 % glucose solution for infusion between administrations of the 2 medicinal products. Day 4 dosing of both medicinal products may be delayed up to 48 hours as medically necessary. Doses of bortezomib should be at least 72 hours apart. The first infusion of SinaDoxosome® should be administered over 90 minutes, as follows:

10 ml over first 10 minutes

20 ml over next 10 minutes

40 ml over next 10 minutes

then, complete the infusion over a total of 90 minutes.

Subsequent doses of SinaDoxosome® will be administered over 1 hour, as tolerated. If an infusion reaction to SinaDoxosome® occurs, stop the infusion and after the symptoms resolve, attempt to administer the remaining SinaDoxosome® over 90 minutes, as follows:

10 ml over first 10 minutes

20 ml over next 10 minutes

40 ml over next 10 minutes

then, complete the remaining infusion over a total of 90 minutes.

Infusion may be given through a peripheral vein or a central line.

3- AIDS Related Kaposi’s Sarcoma

SinaDoxosome® should be administered intravenously at 20 mg/m2 every two-to-three weeks. Intervals shorter than 10 days should be avoided as drug accumulation and increased toxicity cannot be ruled out. Patients should be treated for two-to-three months to achieve a therapeutic response. Treatment should be continued as needed to maintain a therapeutic response.

SinaDoxosome®, diluted in 250 mL 5% Glucose Intravenous Infusion, is administered by intravenous infusion over 30 minutes. 

All Patients

If the patient experiences early symptoms or signs of infusion reaction, immediately discontinue the infusion, give appropriate premedications (antihistamine and/or short acting corticosteroid) and restart at a slower rate.

To manage adverse events such as palmar-plantar erythrodysesthesia (PPE), stomatitis or haematological toxicity, the dose may be reduced or delayed.

Clinical trials

Clinical trial studies comparing Liposomal Doxorubicin HCl with conventional Doxorubicin HCl injectable solution

Liposomal Doxorubicin HCl by Johnson & Johnson company (Caelyx®),

 50mg/m2 every 4 weeks and Doxorubicin HCL, 60mg/m2 every 3 weeks:

1) Cardiotoxicity which is the main adverse reaction of doxorubicin was defined as a decrease of 20%.

2) At cumulative doses greater than 450mg/m2 there were no cardiac events with Caelyx®.

3) Also gastrointestinal adverse reaction decrease significantly in liposomal Doxorubicin HCl in comparison with Doxorubicin.

4) In clinical trial studies the reports showed that nausea which is one of the main complain of Doxorubicin HCl. Showed in 136/225 patients but it decreased to 94/254 in patient receiving liposomal DOX. And Alopecia decreased from 169/225 to 51/254.  

SinaDoxosome® was evaluated in two hospital in Iran; Firoozgar in Tehran and Omid in Mashhad.

In these evaluations there is no report of any unexpected adverse reaction and mortality after SinaDoxosome® injection.

Further investigations are in progress on this formulation in comparison with the brand innovator (Caelyx®).