WO2007072491A2

WO2007072491A2 - Sustained release pharmaceutical formulation and treatment of ischemic heart disease by administering the same

Info

Publication number: WO2007072491A2
Application number: PCT/IN2005/000425
Authority: WO
Inventors: Baskaran Chandrasekar
Original assignee: Baskaran Chandrasekar
Priority date: 2005-12-21
Filing date: 2005-12-21
Publication date: 2007-06-28
Also published as: WO2007072491A3

Abstract

This invention relates to a method of treating ischemic heart disease by stimulating arteriogenesis and angiogenesis. This is achieved by intracoronary administration of a sustained release pharmaceutical formulation containing 17beta-estradiol microencapsulated in biodegradable polymers. A method for stimulation of arteriogenesis and angiogenesis in severe ischemic heart disease by the intra-coronary administration of 17beta-estradiol is described. The 17beta-estradiol is delivered preferably in the form of encapsulated bio-degradable micro-spheres. Intra-coronary delivery of 17beta-estradiol - loaded microspheres can be easily performed during the procedure of cardiac catheterization. The administered 17beta-estradiol - loaded micro-spheres become trapped in the coronary micro-circulation, and undergo gradual degradation producing a sustained concentration of 17beta-estradiol at the level of coronary micro-circulation.

Description

TITLE OF THE INVENTION

Sustained release pharmaceutical formulation and treatment of ischemic heart disease by administering the same.

FIELD OF THE INVENTION

This invention relates to sustained release pharmaceutical formulation containing microencapsulated 17beta-estradiol in bio compatible and bio degradable materials. It also includes a method of treating ischemic heart disease by intracoronary administration of this formulation to patients suffering from severe ischemic heart disease.

BACKGROUND OF THE INVENTION

Revascularization with percutaneous coronary intervention (PCI) and coronary artery bypass surgery (CABG) are effective treatment options for patients with atherosclerotic coronary artery disease. There are, however, a large number of patients with severe illness whose advanced disease makes them unsuitable for either percutaneous coronary intervention or coronary artery bypass surgery. The chronic, severe ischemia in these patients may lead to ischemic cardiomyopathy and other complications, carrying a high morbidity and mortality. Transmyocardial revascularization with laser is an option in these patients. Angiogenesis with basic- and acidic-fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) have been attempted. However, thus far, no form of therapy has demonstrated clear benefit in these patients. The female hormone estrogen is considered to have cardioprotective effects. U.S. Patent No. 5516528 to Hughes et al, describes the use of estrogen in the form of oral, transdermal, or as an implant for reducing the risk of coronary heart disease.

In U.S. Patent No. 6149641 to Ungs, estradiol was injected directly into the arterial wall (intra-mural) proximal to a stenosis or proximal to an ischemic region for stimulation of angiogenesis. The intra-mural drug delivery was performed by special delivery catheters or by means of a stent. Therefore, in this method, drug delivery will be restricted to the level of larger epicardial coronary arteries accessed by these delivery devices which are inherently bulky. This method would result in stimulation of angiogenesis at the site of drug delivery in larger epicardial coronaries only, leaving a large amount of distal myocardium untreated, thereby markedly limiting the utility of this method. Additionally, this method requires the use of expensive delivery devices such as porous balloons, iontophoretic balloons, device with a puncturing element, or drug-coated stents, and, the need for additional clinical competence in the use of such devices. Furthermore, using stents or devices to inject estradiol directly into the arterial wall could potentially result in injury to the vessel wall resulting in neointimal proliferation response at the site of delivery.

In U. S. Patent No. 6443949 to Airman, agents that promote angiogenesis (though 17beta-estradiol is not part of the list of angiogenic factors listed in the citation) were injected by an endocardial hollow penetrating structure directly into the myocardium. This approach has several potential limitations. Direct intra-myocardial (interstitial) injection requires accurate positioning of the endocardial hollow penetrating structure to minimize injury to the myocardium and, proper identification of target area. Ih clinical practice, this process requires very complex and expensive endocardial surface mapping techniques and equipment for proper positioning of the endocardial hollow penetrating structure, and advanced training in the use of such equipment. Furthermore, the vast majority of patients with ischemic heart disease who are candidates for such therapy have extensive disease with multiple and large areas of ischemic myocardium. Multiple intra-myocardial injections of the suspension (of up to 2.0 ml) with the endocardial hollow penetrating structure may result in significant myocardial injury or even myocardial perforation resulting in pericardial tamponade, a medical emergency.

None of the above patents has described the intra-coronary administration of 17beta- estradiol for neovascularization in severe ischemic heart disease. Importantly, it is to be noted that none of the above patents envisages the use of local application of 17beta-estradiol for stimulating arteriogenesis, whereas only the stimulation of angiogenesis has been described. This clearly indicates that the use of local application of 17beta-estradiol was not known as stimulating arteriogenesis. Angiogenesis and arteriogenesis are very distinct phenomena in neovasculariztion, with important differences between the two phenomena (Simons M, et al. Angiogenesis. In: Topol EJ, editor. Textbook of interventional cardiology, 4^th edition; Saunders, 2003:757-779). Angiogenesis is the proliferation of capillaries in the ischemic area, whereas, arteriogenesis is the recruitment and maturation of preexisting collateral vessels (Fujita M, et al. Recent insights into human coronary collateral development. Heart 2004;90:246-250.). The new vessel location in angiogenesis is intra-myocardial, whereas, in arteriogenesis is epicardial. The new vessel wall in angiogenesis is immature and is made up of only endothelial cells, whereas, in arteriogenesis the new vessel wall is mature being made up of endothelial cells, smooth muscle cells, and pericytes. Furthermore, the functional impact of new vessel in angiogenesis is minor, whereas, the functional impact of new vessel in arteriogenesis is major. The functional importance of arteriogenesis in severe ischemic heart disease is such that it is considered as an effective "biologic bypass". It is well recognized in the art that the ultimate aim in neovascularization in severe ischemic heart disease is stimulation of an arteriogenic response, and not stimulation of intra- myocardial angiogenesis (Simons M, et al. Angiogenesis. In: Topol EJ, editor. Textbook of interventional cardiology, 4^th edition; Saunders, 2003:757-779). The present invention describes a simple, inexpensive, and safe method of stimulation of arteriogenesis and angiogenesis in severe ischemic heart disease by intra-coronary administration of 17beta-estradiol.

SUMMARY OF THE INVENTION

Long-term systemic administration of 17beta-estradiol in experimental studies has been shown to stimulate arteriogenesis (Lamping KG, et al. Estrogen therapy stimulates collateral and microvascular remodeling. Am J Physiol Heart Circ Physiol 2003;285:H2039~44). and angiogenesis (ref Morales DE₅ et al. Estrogen promotes angiogenic activity in human umbilical vein endothelial cells in vitro and in a murine model. Circulation 1995;91:755-63; and Jesmin S, et al. In vivo estrogen manipulations on coronary capillary network and angiogenic molecule expression in middle-aged female rats. Arterioscler Thromb Vase Biol 2002,22:1591-1597.). The importance of systemic 17beta-estradiol on arteriogenesis and angiogenesis is emphasized by the evidence that oophorectomy (removal of ovaries) in animals has a negative effect on arteriogenesis and angiogenesis (Kyriakides ZS, et al. Gender does not influence angiogenesis and arteriogenesis in a rabbit model of chronic hind limb ischemia. Int J Cardiol 2003;92:83-91.). 17beta-estradiol enhances transmural myocardial blood flow in ischemic myocardium predominantly through arteriogenesis, and not by angiogenesis (Lamping KG, et al. Estrogen therapy stimulates collateral and microvascular remodeling. Am J Physiol Heart Circ Physiol 2003 ;285:H2039-44.). In addition to arteriogensis and angiogenesis, 17beta-estradiol may also stimulate post-natal vasculogenesis (vasculogenesis is the formation of primary capillary plexus from embryonic stem cells) by mobilization and recruitment of endothelial progenitor cells (Losordo DW, et al. Estrogen and angiogenesis. Arterioscler Thromb Vase Biol 2001;21:6-12.).

The long-term systemic administration of 17beta-estradiol, however, has limiting adverse effects in both male and female gender, and is not feasible in clinical practice. Delivering 17beta-estradiol directly to the desired site of action, namely the coronary micro-circulation, would eliminate the adverse effects associated with systemically administered 17beta-estradiol. As the drug is delivered directly to the desired site of action, the dose of the drug required to produce the desired effect is also markedly reduced, further decreasing the incidence of any possible adverse effect due to the drug. Delivering 17beta-estradiol to the coronary micro-circulation can be easily achieved by injecting the drug into the lumen of the coronary arteries. Although administering 17beta-estradiol solution by this method will deliver the drug to the coronary micro-circulation, the drug would be quickly washed away, thereby resulting in a very brief treatment effect. In order to produce a sustained treatment effect, it is important to increase the residence time of the drug at the desired site of action.

A preferred method of achieving this goal would be to deliver the drug in the form of bio-degradable micro-spheres loaded with 17beta-estradiol. The micro-spheres become trapped in the coronary micro-circulation and gradually degrade over a prolonged period of time, resulting in a sustained release of 17beta-estradiol at the desired site of action, namely, the coronary micro-circulation. The 17beta-estradiol - loaded biodegradable micro-spheres can be prepared utilizing poly(lactide-co- glycolide) (PLGA or PLAGA), or poly(D, L-lactic acid) (PLA), or poly(epsilon- caprolactone) (PCL) as bio-degradable polymers, or, any other bio-degradable polymers capable of encapsulating 17beta-estradiol. The preparation of 17beta- estradiol - loaded poly^actide-co-glycolide) (PLGA or PLAGA), or poly(D, L-lactic acid) (PLA), or ρoly(epsilon-caprolactone) (PCL) bio-degradable polymers has been described and is well known in the art (Xinteng Z, et al. Preparation and evaluation of poly (D, L-lactic acid) (PLA) or D, L-lactide/glycolide copolymer (PLGA) microspheres with estradiol. Pharmazie 2002;57:695-7; Birnbaum DT, et al. Controlled release of beta-estradiol from PLAGA microparticles: the effect of organic phase solvent on encapsulation and release. J Control Release 2000;65:375-87; Mohr D, et al. Gamma irradiation for terminal sterilization of 17beta-estradiol loaded poly- (D,L-lactide-co-glycolide) microparticles. J Control Release 1999;61:203-17; Nowak M, et al. Estradiol and progesterone release form biogegradable d,l-lactide and epsilon-caprolactone copolymer. Acta Pharm Hung 1996;66: 153-6). However, the outer diameter of the 17beta-estradiol - loaded biodegradable micro-spheres of this formulation varies from 10 micrometers to 500 micrometers. The micro-spheres are intended to degrade gradually so as to achieve a sustained release of 17beta-estradiol over a period of a minimum of 15 days to a maximum of 180 days after administration. The dosage of 17beta-estradiol intended to be delivered may be determined by the attending physician taking into account factors such as, body weight of the patient, extent of severity of the coronary artery disease, quantity of ischemic myocardium required to be treated, and other parameters.

Intra-coronary administration of the suspension of 17beta-estradiol - loaded biodegradable micro-spheres can be easily and effectively performed during a cardiac catheterization procedure. The suspension is administered in the form of a slow bolus. The drug may be delivered by means of a catheter, cannula, intra-arterial sheath, or, needle. In another embodiment, intra-coronary administration of 17beta-estradiol may also be performed by means of any vascular device or implant capable of releasing 17beta-estradiol - loaded bio-degradable micro-spheres into the coronary artery lumen. Cardiac catheterization is a very safe, simple, and relatively inexpensive procedure that does not require a high level of expertise. Several million cardiac catheterization procedures are being performed annually all over the world. Intra- coronary administration of the suspension of 17beta-estradiol - loaded biodegradable micro-spheres can also be performed during a percutaneous coronary interventional procedure, or, during cardiac surgery. During a percutaneous coronary intervention, or, during cardiac surgery, the drug may be delivered by means of any catheter (eg. guiding catheter, balloon catheter, transport catheter, infusion catheter, etc.), cannula, intra-arterial sheath, implant device, or, needle.

In another embodiment, the local administration of 17beta-estradiol may be performed with liposomes as drug carriers. It should be noted, however, that the use of liposomes as drug carriers has been associated with important adverse effects such as complement-mediated pulmonary hypertension (Szebeni J, et al. Liposome-stimulated pulmonary hypertension: properties and mechanism of a complement-mediated pseudoallele reaction. Am J Physiol Heart Circ Physiol 2000;279:H1319-28). In another embodiment of the invention, the intra-coronary 17beta-estradiol may be administered in the form of predominantly water-based vesicles, or, derived from amphiphiles.

In another embodiment, for the purpose of stimulation of arteriogenesis and angiogenesis in severe ischemic heart disease, 17beta-estradiol preferably in the form of 17beta-estradiol - loaded micro-spheres may also be administered intra- pericardially, using commercially available designated devices. This approach may be applicable in patients who have not undergone coronary artery bypass surgery in the past.

In another embodiment, 17beta-estradiol preferably in the form of 17beta-estradiol - loaded micro-spheres may also be administered into the lumen of the arteries of the limbs for stimulation of arteriogenesis and angiogenesis in ischemic disease of the limbs (peripheral vascular disease). For this purpose, the drug may be delivered by means of a catheter, cannula, intra-arterial sheath, or, needle. Administration of 17beta-estradiol may also be performed by means of any vascular device or implant capable of releasing 17beta-estradiol - loaded bio-degradable micro-spheres into the lumen of the artery supplying the limb. In another embodiment of the invention, the 17beta-estradiol may be administered in the form of predominantly water-based vesicles, or, derived from amphiphiles.

In another embodiment, the suspension of 17beta-estradiol — loaded micro-spheres may be administered mixed with anti-inflammatory agents (eg. dexamethasone), the anti-inflammatory agent being either in the free form or themselves encapsulated in bio-degradable micro-spheres. The anti-inflammatory agent will help to reduce any inflammatory reaction to the bio-degradable polymer. Alternatively, the antiinflammatory agent may be administered as a separate bolus sequentially following the bolus of suspension of 17beta-estradiol. In yet another embodiment of the invention, a derivative of 17beta-estradiol may be used instead of 17beta-estradiol. The term derivative is intended to include a precursor, an active metabolite, an active analog, or a modulator capable of positively influencing the activity of the receptor(s) to 17beta-estradiol or of enhancing the binding and/or the activity of 17beta-estradiol towards its receptor(s). Such derivatives are considered functional equivalents of 17beta-estradiol, and therefore within the scope of this invention. Such functional derivatives of 17beta-estradiol will be easily obvious to those skilled in the art.

This invention relates to a sustained release pharmaceutical composition which comprises microspheres of 17beta-estradiol or its derivatives encapsulated in biodegradable and bio compatible polymers such as to release said 17beta-estradiol over a period of a minimum of 15 days to a maximum of 180 days of the administration.

This invention also includes a method of treating ischemic heart disease by stimulating arteriogenesis and angiogenesis which comprises the step of intra coronary administration of a pharmaceutical formulation of microspheres of 17beta-estradiol encapsulated in biodegradable and biocompatible polymers.

The invention further includes a method of administering a sustained release pharmaceutical formulation comprising microspheres of 17beta-estradiol or its derivatives encapsulated in biodegradable and biocompatible polymers into coronary artery lumen by catheterization, intra-arterial sheath, cannula, needle or by implant.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Diagram showing injection of suspension of 17beta-estradiol - loaded microspheres into the coronary artery lumen. FIG. 2. Schematic representation of effect of released 17beta-estradiol from 17beta- estradiol - loaded micro-spheres trapped in coronary micro-circulation

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

FIG, 1 shows a catheter 1 during a cardiac catheterization procedure delivering suspension of 17beta-estradiol - loaded micro-spheres 2 into the lumen of the left main coronary artery 3. The 17beta-estradiol - loaded micro-spheres 2 are seen flowing into the divisions of the left main coronary artery 3, namely the left anterior descending artery 4 and the left circumflex artery 5. Distal flow of the 17beta-estradiol - loaded micro-spheres 2 into the coronary micro-circulation 6 is shown representatively in a branch 7 of the left anterior descending artery 4. The trapped 17beta-estradiol - loaded micro-spheres 8 can be seen in the coronary microcirculation 6. A similar injection can be performed into the right coronary artery 9. A suspension volume of 10 ml to 20 ml for the left coronary artery system, and, 5 ml to 10 ml for the right coronary artery system may be administered as slow bolus.

FIG. 2 illustrates the effects of the released 17beta-estradiol 10 from the trapped 17beta-estradiol - loaded micro-spheres 8 in the coronary micro-circulation 6. Upon degradation of the trapped 17beta-estradiol - loaded micro-spheres 8, 17beta-estradiol is released into the coronary micro-circulation 6. The released 17beta-estradiol 10 enters into the vessel wall 11 of the coronary micro-circulation 6. The released 17beta- estradiol 10 has multiple effects. It acts on the capillary vessels 12, stimulating fresh tubule formation resulting in new capillary vessel proliferation 13. This process of new capillary vessel proliferation is termed "angiogenesis". The released 17beta- estradiol 10 also acts on pre-existing immature collateral vessels 14 that permit only a small amount of blood flow 15 (represented by thin arrow) before the effect of released 17beta-estradiol 10. Following the action of the released 17beta-estradiol 10, an enhancement is seen in the amount of blood flow 16 (represented by thicker arrow), and, the collateral vessels show remodeling (maturation) of the vessel wall by way of increased thickness 17 due to proliferation of smooth muscle cells and pericytes. This process of remodeling (maturation) of collateral vessel wall and enhanced blood flow is termed "arteriogensis". The released 17beta-estradiol 10 also stimulates mobilization and recruitment of endothelial progenitor cells 18, leading to "vasculogenesis".

Although the invention has been described in detail with particular reference to these preferred embodiments, other embodiments can achieve the same results. Variations and modifications of the present invention will be obvious to those skilled in the art and it is intended to cover in the appended claims all such modifications and equivalents.

Claims

1. Sustained release pharmaceutical formulation which comprises microspheres of 17beta-estradiol or its derivatives encapsulated in biodegradable and biocompatible polymers such as to release said 17beta-estradiol over a period of a minimum of 15 days to a maximum of 180 days after administration.

2. The pharmaceutical formulation as claimed in claim 1, wherein said biocompatible and biodegradable polymers are estradiol - loaded poly(lactide- co-glycolide), poly(D, L-lactic acid), and poly(epsilon-caprolactone).

3. The pharmaceutical formulation as claimed in claim 1 wherein the outer diameter of said microspheres are in the range of 10 micrometers to 500 micrometers.

4. A method of treating ischemic heart disease by stimulating arteriogenesis and angiogenesis comprising the step of intracoronary administration of a pharmaceutical formulation of microspheres of 17beta-estradiol encapsulated in biodegradable and biocompatible polymers.

5. The method as claimed in claim 4, wherein said formulation is administrated in the form of a slow bolus.

6. The method as claimed in claim 4, wherein said formulation is administered by means of a catheter, cannula, intra arterial sheath or a needle.

7. The method as claimed in claim 4, wherein said drug is administered by means of a vascular device or an implant capable of releasing a pharmaceutical formulation into the coronary artery lumen

8. A method of administering a sustained release pharmaceutical formulation comprising microspheres of 17beta-estradiol or its derivatives encapsulated in biodegradable and biocompatible polymers into coronary artery lumen by catheterization, intra arterial sheath, cannula, needle, or by implant.