Pharmaceutical formulation applied for prevention and treatment of bone tissue resorption of any etiology, transdermal delivery and treatment technique

FIELD: medicine; pharmacology.

SUBSTANCE: given invention refers to pharmaceutical field, specifically to pharmaceutical formulation of gel dosage form applied for prevention and treatment of osteoporosis including as an active component bisphosphonate incorporated in phospholipid vesicles generated from lipid and hydrophilic phases, including components in the following proportions, mass %: bisphosphonate 0.01-2.0; egg lecithin 1.0-6.0; pine essence 0.05-0.2; camphor oil 0.01-1.0; olive oil 0.01-5.0; vitamin E 0.01-0.15; vitamin D 0.01-0.2; vitamin F 0.2-0.4; carbopole 0.4-0.6; NaOH 0.42; glycerol 2.0-4.0; nipagine 0.3; nypazole 0.1; water and others. In addition invention refers to treatment of bone tissue resorption of any etiology and osteoporosis for patients suffering from gastrointestinal disturbance with this composition.

EFFECT: high concentration of bisphosphonate inside of tissues and bones directly in and around medicine application onto the skin without necessity to apply additional medical equipment or techniques.

10 cl, 2 dwg, 3 ex

The invention relates to medicine, namely to medicines and compositions used for the prevention and treatment of bone resorption, such as osteoporosis, Paget's disease, pathological fractures in cancer patients, as well as to prevent osteoporosis in menopausal period.

Alendronate sodium when introduced into the body of warm-blooded shows osteocalcine and interacts with the bone tissue as a specific inhibitor of osteoclast mediated bone resorption. As a synthetic analogue of pyrophosphate, alendronate sodium specifically binds to the hydroxyapatite of the bone, which inhibits bone resorption.

However, alendronate sodium, as the drug has significant disadvantages, for example, extremely low oral bioavailability (<1%), it often causes complications associated with irritation and ulceration of the mucous membranes of the gastrointestinal tract, and therefore cannot be assigned a significant group of patients suffering from gastrointestinal diseases.

It is generally accepted that the ingress of bisphosphonates in the systemic circulation, even when administered intravenously, is not a key moment in the treatment of osteoporosis or other diseases with bone resorption, the main business is shipping, distribution, exposici is of bisphosphonates on the surface porozni bones.

It is known that bisphosphonates can be absorbed when applied to the skin. Optimization methods of penetration through the skin salts, diphosphonic acids of the proposed Ferrini P.G. et al., (EP 0407344, published on February 27, 1991).

The disadvantage of this method is that bisphosphonates as part of the proposed formulations hardly penetrate into the subcutaneous fatty tissue and quickly helps eliminate from the "depot", in addition, to optimize transdermal transport are additional components that can cause skin irritation or allergic reactions.

Proposed method of local application of alendronate sodium by delivery via the mucous membranes of the vagina in the composition of vaginal suppositories, soft gelatin capsules or cream (patent US 6905701, published 14 June 2005). However, this method has significant drawbacks associated with the irritant effect of alendronate on the mucous membranes and restrictions on the use of the drug associated with the floor of the patient.

The prior art known to the local use of alendronate sodium for the prevention and treatment of bone resorption various etiologies, where delivery of the active component by using iontophoresis (patent US 6008206, published on December 28, 1999). The lack of supply is that the delivery of alendronate sodium by way of iontophoresis allows to obtain n the significant concentration of the drug at the injection and requires special medical equipment.

The closest in technical essence of the present invention is a pharmaceutical composition for the treatment of osteoarthritis and osteoporosis of various etiologies, containing alendronate sodium, white petrolatum, salicylic alcohol, white beeswax, glycerin, liquid paraffin, laurilsulfate of sodium and water, and how local use of alendronate sodium, including selective delivery of the drug to sites of increased bone resorption (patent US 5958908, published on 28 September 1999).

The disadvantages of this composition and method of application is the inability to provide the necessary concentration of alendronate sodium in the tissues and the bones directly in the area of localization of the pathological process due to the low penetrating power of the active substance in the composition of the framework proposed by the authors.

The technical result of the claimed invention lies in the fact that the proposed composition for transdermal delivery allows to provide a high enough concentration of alendronate sodium in the tissues and the bones directly in the field of application of the drug to the skin, without the use of additional medical equipment or techniques (iontophoresis, electrophoresis, massage rubbing, injecting drug use).

The objective of the proposed izobreteniya the creation of a pharmaceutical composition of alendronate sodium drug in the form of a gel for transdermal applications, in which alendronate sodium or other bisphosphonates are in liposomes significantly enhance the bioavailability of alendronate sodium and creating conditions for long-term local preservation of therapeutic concentrations of alendronate sodium in areas of bone resorption different etiology, pathological fractures and other conditions associated with a need for reparation of bone tissue.

The above result is achieved by the fact that in the claimed pharmaceutical compositions for the prevention and treatment of bone resorption various etiologies, containing the active component, alendronate sodium, the latter incorporated into phospholipid vesicles formed from lipid and hydrophilic phases, the lipid phase includes: egg lecithin, essential oils of pine, camphor and olive oil, vitamins E, D, F, and hydrophilic - alendronate sodium, advanced composition contains a gelling including carbopol, NaOH 10%, the plasticizer is glycerol, preservatives, nipagin, nipazol and water in the following ratio of components in the composition, wt.%:

the components are processed in high-speed homogenizer, which formed a monolayer of liposomes of defined size, which are the result of processing of fat-soluble ingredients.

The result is achieved by the fact that the pharmaceutical composition comprising liposomes with alendronate sodium in gel, applied to the skin directly in places diagnosed resorption of bone (fractures, joints, vertebrae, etc.).

The active transport of drugs and biologically active substances in liposomes has been proved many times (for example, patent RF №2167650, BI, No. 15, 2001). Using the conclusion in liposomes not only managed to deliver the drug to the target organs, but also in many cases significantly reduce their required concentration, which is very important in cases of use of medicines in the region of the giving side effects.

The present invention aims at obtaining a liposomal pharmaceutical compositions of bisphosphonates for transdermal transport, comprising as active ingredients: alendronate, risedronate, etidronate, clodronate, pamidronate and other proposed conditions associated with bone resorption as a result of osteoporosis and bone regeneration in pathological fractures, osteoplasty and other

The composition of the proposed pharmaceutical composition comprising a gel, a plasticizer, a lipid phase, a hydrophilic phase, bisphosphonates, preservative, essential oil and water is represented by the examples.

Example 1.

Example 2.

Example 3.

Pharmaceutical composition with alendronate sodium, included in vesicular particles of very small size (from 50 to 250 nm), stable in the system of polymers of different nature, acting as an inhibitor of osteoclast mediated bone resorption, can be used for the correction of bone resorption in women in postmenopausal period. The application of the proposed composition significantly reduces the amount of compression fractures of the spine and femur neck and reduces the porosity of the bones in older age in women as well as men.

Liposomal composition with bisphosphonates, which are used in the form of a gel, provides high bioavailability and active transport of the composition in the deeper layers of subcutaneous tissue and tissue surrounding the bone.

Transdermal delivery composition is easily accomplished by applying a certain amount of gel containing a stable suspension of liposomes on the skin areas diagnosed with a porosity of bones or reparation of bone tissue as a result of fractures.

The use of liposomes allows you to optimize the concentration of active substances in the composition of the gel, which allows to achieve a maximum therapeutic effect, and also to carry out transport bisphosphonate is in a certain area of the spine, bones, joints and tissues surrounding ponosnye or deformed bones.

Offer liposomal composition allows to effectively use the properties of alendronate sodium or other bisphosphonates, to apply additional active substances, and to eliminate the deficit of phospholipids in places of gel.

The method of delivery of alendronate sodium to sites of bone resorption is to apply a certain amount of liposomal gel with bisphosphonates on the skin in the area of bone defects, compression fractures of the spine and femur neck, or over the place of reparation of bone tissue in the treatment of fractures or osteoplasty.

The method of obtaining the composition is as follows. First dispersed input components of the pharmaceutical composition of the above recipe. Received a suspension of liposomes with incorporated alendronate sodium, stabilize the gel, type plasticizer glycerol and preservatives.

The technological process is as follows.

1. Preparation of the ingredients.

1.1. Dissolution of the polymer.

1.2. The mixture of glycerol preservative.

1.3. Mixing auxiliary components: egg lecithin, oils of olive, castor, essential oils of pine, vitamins E, D, F.

2. Mixing the hydrophilic and g is grafalloy phases.

Mixing is carried out in the high-speed homogenizer at room temperature. In the willing suspension of lipid vesicles obtained by the method of neutralization, add the active ingredient. Homogenization is carried out at maximum mode speed mixer for 5-10 minutes Then add the preservative complex and stirred the mass in the control pH of 6.9 to 7.4.

The whole process can be performed on the installation type PHS-2 with generator acoustic oscillations or if effective mixer-homogenizer to obtain liposomes can be used a method of ultrasonic processing or extrusion technique through membrane filters.

The size and elanet liposomes monitored by electron microscopy or by spectrophotometry.

Clinical and other tests.

The efficacy and safety of the gel form of bisphosphonates tested on volunteers.

Clinical trials of farbkomposition was carried out on 62 volunteers, women and men, different age categories: from 32 to 75 years, with various bone health. The term clinical trials of at least six months. The clinical status of probando was estimated with the frequency of monitoring once a month compared with the control (well-known means and methods for the prevention and treatment of bone resorption).

The first stage, before clinical testing, all patients were put on a skin allergic test with experimental gel. In any case, signs of skin irritation and allergic reactions to local or General nature were not observed.

Professionals engaged in clinical trials, as well as by the subjects, it was noted that the tool is convenient in practical application, including massage.

Patient B., aged 53 years, osteoporosis amid immunopathy, constant aching pain in the tubular bones. Application of the gel with alendronate sodium greatly facilitated the patient's condition after 1.5 months of treatment: joint mobility increased, decreased swelling and pain.

Patient G., 66 years old, diagnosis: osteoarthritis of the knee joint on the right.

Application of the gel with alendronate sodium for three months significantly improved the patient's condition: registered decrease in pain, decrease swelling, increase bone density by densitometry.

Patient A., aged 55 years, the diagnosis of osteoporosis in the postmenopausal period. To facilitate the state was appointed gel with alendronate sodium, skin application was performed to the patient daily for three months.

At follow-up the patient after three months, there were positive changes in densitogram, led the increase of range of motion in the knee and hip joints, the increased tolerance to stress.

Research pharmakinetic of liposomal farbkomposition with alendronate sodium in vivo studies were performed at research Institute of pharmacology RAMS them. You using a radioisotope method 152 outbred white rats weighing 180-220 g tritium-Labeled alendronate sodium with a specific radioactivity 30 µci/mg at a dose of 1 mg used for oral administration and application on the skin in the form of a gel, in which alendronate sodium with a radioactive label was in liposomes.

Figure 1 shows the kinetic curves of concentrations of alendronate sodium in the plasma of experimental white rats after its oral administration, single and quintuple the application to the skin of the inner thigh in the composition of the liposomal gel.

The content of the labeled products were determined in plasma, muscle and bone tissues of rats, urine and faeces. The samples were analyzed through 2, 4, 8, 12, 24, 48 and 72 hours after administration of the drug inside and skin application gel on pilirovanny inner thighs laboratory animals.

Figure 2 presents the kinetic curves of concentrations of alendronate sodium in the plasma of Wistar rats, the muscle tissue of the hips and thighs after five cutaneous application of alendronate sodium in the composition of the liposomal gel in the area of the inner thigh of rats at a dose of 1 is g (4,80± 0,34 mg/kg).

As a result of experiments, it was found:

- proposed composition refers to "long-lived" and is defined in the body of rats within 72 hours,

the relative bioavailability of alendronate sodium after his five-time application to the skin of rats in the composition of the gel in 2,63 times higher compared to a single application and 1.46 times higher compared to peroral,

- cutaneous application of alendronate sodium drug in the form of the gel leads to doubling of the period of preliminary of the drug compared with oral its introduction.

1. Pharmaceutical composition in dosage form gel for the prevention and treatment of osteoporosis and other conditions associated with a need for reparation of bone tissue, comprising as an active ingredient a bisphosphonate, wherein the bisphosphonate incorporated into phospholipid vesicles formed from the lipid and the hydrophilic phase comprising components in the following ratio, wt.%:

2. Pharmaceutical composition in dosage form gel according to claim 1, wherein the bisphosphonate is selected from the group of: alendronate, risedronate, etidronate, clodronate, pamidronate.

3. Pharmaceutical composition in dosage form gel according to claim 1, characterized in that the dimensions of phospholipid vesicles comprising a bisphosphonate, is in the range from 50 to 250 nm.

4. The method of treatment of bone resorption different etiology, characterized in that the pharmaceutical composition in dosage form gel according to claim 1 appliciruut skin in places diagnosed resorption or destruction of bone.

5. A method of treatment of osteoporosis in patients with pathology of the organs of the gastrointestinal tract, characterized in that the pharmaceutical composition in dosage form gel according to claim 1 appliciruut transdermal.