Patent Application
20080050436
This invention is about a new treatment method for hemorrhoids, venous insufficiencies, varicose vein, esophageal varices, venous-drainage-impotence of the penis, vascular malformation, and excessive blood supplied to tumors. The present invention solves many of the problems inherent in the art by providing a biocompatible, injectable thickener to increase the viscosity of the sclerosant/thickener compound without the need to form foams when the compound is injected into the blood vessel. Aspects of the present invention encompass a new biocompatible, injectable non-foaming sclerosant/thickener compound intended for use in sclerotherapy to irritate, dehydrate, change the surface tension of or destroy the endothelium cells. This causes a localized inflammatory reaction and produces small thrombosis that eventually results in permanent fibrosis and elimination of the vein.
The new thickener/sclerosant compound has a relatively higher viscosity than the blood. Without the gas bubbles in it, it is stronger than the foams and can replace blood in the vessel more effectively while injected. As a result, the dilution and diffusion of the sclerosant in the blood is reduced, and the vessel wall is exposed to a controlled concentration of sclerosant during the treatment. Due to this reduced dilution compared with current method, a lower concentration of injected sclerosant can be use in this new therapy. Because of the relatively lower solubility of the thickener/sclerosant compound in the blood, the contact time between the sclerosant and the vessel wall is increased. More injury to the endothelium is expected by the longer exposure to the sclerosant. This can enhance the efficiency of sclerosant and further reduce the concentration of the sclerosant required in this treatment.
Viscosity is a property of fluid related to the internal friction of adjacent fluid layers sliding past one another as well as the friction generated between the fluid and the wall of the vessel. The viscosity of a fluid is basically a measure of how sticky it is. The viscosity of water is about 1 cPs (or 1×10−3 Pa s) at room temperature. Blood viscosity is a complicated function of hematocrit, shear rate, and blood composition. Whole blood has a viscosity of 3 to 4 cPs (or 3 to 4×10−3 Pa s) depending upon hematocrit, temperature and flow rate.
The equation that governs fluid flowing through a pipe or tube is known as Poiseuille's equation. It is only valid for streamline flow in the tube. Although blood flow through blood vessels in the human body isn't exactly streamline, but applying Poiseuille's equation in this situation is a reasonable first approximation.
Q=πR
4(P1−P2)/(8 μL)
Where Q is the volume rate of the flow, R is the radius, (P1-P2) is the pressure difference between the ends of the tube, L is the length of the tube, and μ is the coefficient of viscosity. The most interesting thing to notice about the volume rate of flow is that it's inversely proportional to the viscosity. A fluid with a higher viscosity has a lower flow rate. In a blood vessel with both fluids, the fluid with a lower viscosity has a higher flow rate and will leave the fluid with a higher viscosity behind. Eventually, the blood vessel will be filled with a fluid with a higher viscosity. This is the reason why we would like to use the thickener to increase the viscosity of the sclerosant. The sclerosant/thickener compound can replace the blood in the vessel when its viscosity is higher than the blood. In this invention, the viscosity of the sclerosant/thickener is higher than 4×10−3 Pa s and preferably higher than 6×10−3 Pa s. Poiseuille's equation can also be used to explain the issues with current sclerotherapy. For a typical sclerosant, it is usually diluted by saline or water to reach the target concentration and for the ease of injection through a needle. The viscosity of the resulting solution is usually lower than the blood (typically around 2×10−3 Pa s). This solution has a higher flow rate than the blood and is more likely to be diluted by the blood right after the injection and released the sclerosant in the blood. As a result, it is easy to understand why dilution is a problem with the current sclerotherapy.
The present invention solves many of the problems inherent in the art. For example, the sclerosant/thickener compound is stronger than the foams and can displace the blood more effectively and is not diluted until it is dissolved or bio-resorbed. Compared with the lighter weight foams, the thickener is less likely to move with the blood flow, and thus the contact time between the sclerosant and the vessel wall is better controlled. This enhanced control in both concentration and treatment time can significantly reduce complications due to the uncertainties in injecting during the conventional sclerotherapy or foam sclerotherapy as mentioned above. Because the sclerosant is embedded in the thickener, treated zone is the vessel length filled with sclerosant/thickener. The sclerosant concentration of the ‘run-off’ sclerosant outside the treated zone or in the deep vein comes out slowly and is diluted to an in-effective concentration. This will enhance the safety and controllability of the sclerotherapy and reduce the chance for vessel injury outside the target area or deep vein thrombosis. On the contrary, the scleroant foams are weaker than the sclerosant/thickener and tend to break up easily. The “broken up” foams clusters still have a relatively high local sclerosant concentration and may flow to other organs (or deep veins) and cause damage to them.
This invention also enables the use of sclerotherapy for large vessels which can not be treated by foams sclerotherapy. Because the sclerosant/thickener is stronger than the foams and not diluted in the blood and maintains a close contact with blood vessel, potentially less sclerosant is needed to treat varices. In addition, the dissolving (or resorbing) rate of the sclerosant/thickener can be controlled to achieve the optimum treatment time without the issue of sclerosant ‘run-off’. More injury to the endothelium is expected by the longer exposure to the sclerosant/thickener. This can enhance the efficiency of sclerosant and further reduce the concentration of the sclerosant required in this treatment. As a result, the incidence and severity of complications that are created by the high dose of sclerosant used in the current foams sclerotherapy can be reduced. Due to the enhanced safety and controllability with the new invention, large varices can be treated with this new sclerosant/thickener without the issue of sclerosing the deep veins.
Sclerosants can be classified into detergents, chemical irritants, and osmotic agents. Their mechanisms to produce endothelial injury vary with these agents. They also vary in their sclerosing power, concentration, the pain provoked on injection and the incidence of other adverse effects. Although a variety of sclerosants are currently available, the ideal agent is yet to be developed. There is no consensus regarding the use of a specific sclerosant, its concentration of dose and for which specific type of varicose veins (part of the reason for this is the lack of sclerosant control during the therapy as mentioned before). The concentration and injection volume of the sclerosants also depends on the interval between injections and whether it is the first injection or re-injection. The most commonly used sclerosing agents are sodium tetradecyl sulfate (STS), sodium salicylate, salicylic acid, hydroxy-polyethoxy-dodecane, hypertonic saline, polidocanol (POL), chromated glycerine, alkali metal tetradecyl sulfate, ethyl alcohol, invert sugar, ethanolamine oleate, sodium morrhuate, polyiodinated solution, Polyiodine iodine, polydodecane, iodic solutions, non-necrotic fatty acid compound (such as sodium oleate, sodium psylliate, sodium ricinoleate, ethylamine oleate, monoethanolamine oleate, sodium formate, sodium acetate and calcium propionate), tetracycline, ferric chloride, quinine, urea, or the combination of the above. The following table lists the concentration of some typical sclerosant used in current sclerotherapy when water or saline (low viscosity) is used as carrier.
The preferred thickener in this invention should be biocompatible. When it is mixed with sclerosant, the compound should have a higher viscosity than the blood and a slower blood solubility rate at 37° C. As a result, the sclerosant/thickener compound is able to form a plug in the vessel after injection with a needle or a catheter and replace the blood in the treated vessel without being diluted before it is dissolved eventually. Many factors affect the viscosity of the thickener. They are the concentration of the thickener, solubility in the blood, molecular weight, temperature, crosslinking agent, process condition, the type and amount of additives and sclerosant in the thickener, etc. The other requirement for sclerosant/thickener is that it should be a fluid with viscosity lower enough before it contacts with the blood so that it can be injected through a needle or a catheter. The sclerosant/thickener should be able to inject at a sufficient rate to fill the vascular lumen before being carried away by blood flow. Once injected in the vessel, the thickener should maintain its properties until it is diluted by the blood. Lastly, it is desirable to have a thickener that can be dissolved or resorbed in the blood after the treatment, because a relatively thickener free vessel is needed after sclerotherapy for the fibrosis to occur on the vessel wall.
The injectable thickeners disclosed herein are biocompatible and preferably biodegradable. The thickener is preferable substantially free of impurity and preferable employed in a highly purified form. They do not cause toxic or inflammatory effects and substantially, if not completely, are degraded, excreted or metabolized by the body. This process may typically take up to several days and is regulated by variables in the formulation and manufacturing of the injectable thickener disclosed herein. The degradation by-products may be mainly expelled via normal respiration and excretion. Many thickener can be used for this application. The following sections will discussed the materials in details.
Viscosity of the compositions may be maintained at the selected level using a pharmaceutically acceptable thickening agent. The thickeners including Acacia, Agar, Alamic Acid, Alginic Acid, Aluminum Monostearate, Attapulgite, Activated Attapulgite, Carbomer Copolymer and Homopolymer, Carbomer Interpolymer, Carboxymethylcellulose (CMC), Carboxymethylcellulose Calcium, Carboxymethylcellulose Sodium, Carrageenan, Cellulose Microcrystalline, Dextrin, Gelatin, Gellan Gum, Guar Gum, Hydroxypropyl Methylcellulose, Hypromellose, Maltodextrin, Methylcellulose, Pectin, Polyethylene Oxide, Povidone, Propylene Glycol Alginate, Colloidal Silicon Dioxide, Sodium Alginate, Tragacanth, Xanthan Gum, Polyacrylic acid, Polyethylene glycol(PEG), lecithin, tridobenzene derivatives, iohexol, iopamidol, iopentol, glycogen, acetyl starch, sucrose, glucose, mannitol, saccharin sodium, dextran, dextrose, sorbitol, phospholipids, cephalin, acetylenic diol, albumin, cellulose derivatives, ethylcellulose, alkyl cellulose, alkoxy cellulose, polyorgano sulfonic acid, and alkoxylated surfactants and their mixtures. The alkoxylated surfactant include, but are not limited to, the group consisting of alkylphenol ethoxylates, ethoxylated fatty acids, alcohol ethoxylates, alcohol alkoxylates, and ethylene oxide-propylene oxide copolymers (Poloxamers, Tetronics or Pluronics). Albumin, Poloxamers, Pluronics, dextran, gelatins and acetyl starch are preferred because they are readily and economically available and are easy to work with. The viscosity of some typical thickeners are listed in Table 2.
Viscous compositions can be formulated within the appropriate viscosity range to provide longer contact periods with vessel wall. Obviously, the choice of suitable thickener and other additives will depend on the exact method of administration and the nature of the sclerosant. The preferred concentration of the thickener will also depend upon the sclerosant selected. The important point is to use an amount which will achieve the selected viscosity. Viscous compositions are normally prepared from solutions by the addition of such thickening agents. The viscous compositions will typically contain a sufficient amount of a thickening agent so that the viscosity is from about 4 to 100 cPs for needle delivery, although more viscous compositions, even up to 2,000 cPs, may be employed for catheter delivery. It is preferably to have a viscosity of 5 to 600 cPs, since above that range it becomes more difficult to inject. For a high concentration of thickener, less dilution in the blood will occur and less sclerosant is required. However, a less amount of thickener should be used if a small gage needle is used to administer the sclerosant/thickener compound in the vessel. The thickening agent is typically present in a concentration of from about 0.01-80% by weight in the water or other pharmaceutically acceptable carrier, more typically from about 0.05% to about 40%. The sclerosant/thickener compound can be injected into the target vessel through a needle or a catheter. Because the higher viscosity (and lower solubility) of the sclerosant/thickener compound compared with blood, it replaces blood and forms a plug in the vessel. The sclerosant in the compound is then released into the vessel wall or blood stream either by diffusion or by dissolving of the thickening agent(s). The release rate of the sclerosant can be controlled by tailoring the composition, the type of sclerosant and molecular weight of the thickening agent(s).
Hydrogels are attractive for different biomedical applications because their favorable biocompatibility. They play an important role in controlled drug delivery because of their pertinence in delivering delicate bioactive agents such as proteins. Hydrogels are network of hydrophilic polymers that can swell in water and hold a large amount of water while maintaining that structure. A three dimensional network is formed by crosslinking polymer chains. The crosslinking can be provided by covalent bonds, hydrogen bonds, van der waals interactions or physical entanglements. Depending on the crosslinking density and molecular weight, the viscosity of the hydrogel can be very high or lower enough to be delivered through the needle or catheter. Examples of some suitable hydrogels for thickeners are polyvinyl pyrrolidone (PVP) polymer or copolymer, polyethylene oxide (PEO) polymer or copolymer, poly(propylene oxide), poly(propylene glycol), poly vinyl alcohol (PVA) polymer or copolymer, Hyaluronic Acid (HA), polyacrylamine, poly(vinylcarboxylic acid), polymethacrylic acid, polyacrylic acid polymer or copolymer, poly amino acids, gel, collagen, fibrin, bioglue, gelatin, alginate, calcium alginate, Cellulose acetate phthalate, cellulosics, Carbopol, Poloxamer, Pluronic, Tetronics, PEO-PPO-PEO triblocks copolymer, tetrafunctional block copolymer of PEO-PPO condensed with ethylenadiamine, polyhema polymer or copolymer, Hypan polymer or copolymer, starch glycolate polymer or copolymer salt, dextran polymer or copolymer, polyoxyalkylene ether, polyvinyl pyridine, polylysine, polyarginine, poly aspartic acid and poly glutamic acid, polytetramethylene oxide, poly(hydroxy ethyl acrylate), poly(hydroxy ethyl methacrylate), hydroxy ethyl cellulose, hydroxy propyl cellulose, methoxylated pectin gels, carrageenan, agar, agarose, oligosaccharide, and macrocyclic polycsaccharide. Alternatively, various hydrogels can be mixed together to tailor the viscosity and the dissolving or resorbing rate in the blood. For example, the PVP can be combined with the Pluronic to increase the dissolving and drug release rate of Pluronic.
The hydrogel can be used as it is or mixed with saline, water, alcohol or other physiological solvents to modify the viscosity of the sclerosant and the dissolving or resorbing rate in the blood. It is mixed with the selected sclerosant and then injected into vessel by either a needle or a catheter. A suitable concentration of the hydrogel will be from 0.01% to 80% based on the total weight and the sclerosant selected. Because the higher viscosity (and lower solubility) of the hydrogel/sclerosant compound compared with blood, it replaces blood and forms a plug in the vessel. The sclerosant in the compound is then released into the vessel wall or blood stream either by diffusion or by dissolving of the hydrogel(s). The release rate of the sclerosant can be controlled by tailoring the composition, crosslinking density, the type of sclerosant and molecular weight of the hydrogel(s). It is known that the release rate of the sclerosant is faster when the sclerosant is relatively small or the hydrogel has a lower crosslinking density. The example of this embodiment is PVP as thickener. It is mixed with sclerosant, saline, water, buffer agent, etc. for a higher viscosity. The preferred viscosity of the final compound is higher than 4×10−3 Pa s which is blood viscosity at 37° C. The sclerosant/PVP compound can be injected into the vessel with a needle. Because the sclerosant/PVP compound has a higher viscosity compared with blood, it will form a plug immediately. The sclerosant is then released into the vessel wall through diffusion and as PVP is resorbed into the blood.
Alternatively, some hydrogels require additional curing or crosslinking agent to reach a higher viscosity if it is needed. For those multi-components hydrogels, the sclerosant can mix with component(s) of the hydrogel without causing it to gel. Then, the liquid mixture is injected into the target site to mix with other component(s) of the hydrogel to gel in situ and form a plug of hydrogel/sclerosant. The benefit of this approach is the relatively easier injection through a needle or a catheter due to the lower fluid viscosity of the component(s) before gelling. After the polymerization (or gel or crosslink), the viscosity of the sclerosant/polymer increases, and the solubility of the sclerosant decreases significantly. The example of this embodiment is Ca+2 Alginate. The Alginate solution can be mixed with a sclerosant (without causing gelling) and be injected into the vessel with a needle or a catheter. Ca+2 solution is a typical crosslinking agent for Alginate. It can be injected into the target vessel with a needle or a catheter to mix with the Alginate/sclerosant solution and form a gel in the vessel. The resulting sclerosant/Ca+2 Alginate has a higher viscosity compared with blood and forms a plug immediately. The sclerosant is then released into the vessel wall through diffusion and as Alginate is resorbed into the blood. It is also part of this invention if the sclerosant is mixed with the Ca+2 and then injected into the vessel to mix with Alginate, which is injected separately.
In many situations, hydrogel dissolving in the pharmaceutically acceptable carrier (water, saline) will provide solution viscosity higher than the blood at 37° C. and can be used as thickener for sclerosant. However, it will be ideal to have a sclerosant/thickener formulation with a relatively lower viscosity that can be passed through a needle or catheter for injecting into blood vessels without much effort. After it is in the body, the sclerosant/thickener can change into a higher viscosity material (a gel, etc.) due to the change in temperature, pH, antigen, glucose, or salt content, etc. and replace the blood in the vessel.
Many physical and chemical stimuli have been applied to induce various responses of the environmentally sensitive hydrogels. Physical hydrogels formed with change in temperature, electric field, solvent composition, light, pressure, sound and magnetic field. The chemical stimuli include pH, ions, or salt content, etc. Some of the pH sensitive polymer solutions are: Cellulose acetate phthalate, Carbopol, etc.
The temperature sensitive polymers are part of the ESH and have been studied as potential injectable drug delivery carrier for treating other diseases. They are usually made of polymer with moderate hydrophobic groups or a mixture of hydrophilic and hydrophobic segments. One example is triblock (ABA) copolymers of polyethylene oxide-polypropylene oxide-polyethylene oxide (Poloxamers, Tetronics or Pluronics). They are non-ionic surfactants widely used for medical applications. Some of them have reversible temperature sensitive properties. They form gels at high concentrations and elevated temperatures (higher than the lower critical solution temperature, LCST). At the elevated temperatures, the hydrophobic interaction between the PPO segments of PEO-PPO-PEO triblocks copolymer facilitates the formation of the polymer network while the hydrogen bonding between the polymer and the water becomes weaker. This creates a sudden transition as the hydrated hydrophilic polymer quickly dehydrates and changes to a gels-like structure with a higher viscosity. At a lower temperature, hydrogen bonding between hydrophilic segments of the polymer chain and water molecules dominates and resulting enhanced dissolution and a lower viscosity. This type of thermally reversible polymer can be formulated to allow the injection of a liquid form, through a small catheter or needle at room temperature, which can gel at body temperature.
The LCST of the hydrogel can be altered by changing the polymer composition (hydrophilic/hydrophobic segments ratio and molecular weight). As the polymer chain contains more hydrophobic constituent, LCST becomes lower. Several types of Poloxamers (Poloxamer 188 and 407, Pluronic F127, PF127) have LCST around the body temperature. A preferred Poloxamer according to this invention is Poloxamer 188; a poly(oxyethylene)poly(oxypropylene)copolymer wherein the poly(oxypropylene) portion has an average molecular weight in excess of 12,600 and the polyoxyethylene portion amount to 30% to 70% by weight. The thermo-reversible transition is about 37° C. for a solution of 20% concentration. Another preferred poly(oxyethylene)poly(oxypropylene)copolymer is Pluronic F127. It has an average molecular weight of from about 7500 to about 15,500 with more than 50% oxyethylene units in the total molecular. Its thermo-reversible transition is from about 25° C. to 40° C. for a solution of from 10% to 26% wt in the water. When the thermally reversible hydrogel is used as thickener, it is mixed with sclerosant to form a solution at lower temperature (lower than LCST of the thickener). After the sclerosant/thickener is injected into the blood vessel, it will form a gel immediately and block the blood flow.
In addition to PEO-PPO block copolymers (Poloxamers, Tetronics or Pluronics), their derivatives also process reverse thermo-responsive properties. Cohn, et al. (2003) investigated the bulk polymerization of PEO-PPO-PEO with hexamethylene diisocyanate (HDI) and using phosgene to connect covalently poly(ethylene glycol) and poly(propylene glycol) chains. The new polymers showed reversible thermo-response around 37° C. with much higher viscosities than Pluronic F127. As a result, a lower concentration of the new polymer is required to achieve the same viscosity with F127. The drug release rate in this type of copolymers was slower compared with F127 at the same concentration.
Other than PEO-PPO-PEO triblocks copolymers, the hydrophobic segment (PPO) can be replaced with other hydrophobic polymers and still demonstrate similar thermal reversible properties. Triblock copolymers consisting of poly(ethylene glycol) and other biodegradable polyester blocks, such as poly(L-lactic acid) or poly(glycolic acid), or their co-polyesters were reported to show temperature-dependent reversible sol-gel transitions. Poly(acrylic acid) grafted (PEO-PPO-PEO-PAA) copolymers also have similar transition property and were studied as potential injectable drug delivery vehicles. Many other polymers have similar thermo-responsive phenomenon. They are: graft copolymers of Pluronic and poly(acrylic acid), ethyl(hydroxyethyl) cellulose (EHEC) formulated with ionic surfactants, alkylcellulose, hydroxyalkylcellulose, PEG-PLA-PEG block polymers, Poly(N-isopropylacrylamide)(PNIPAAm), tetrafunctional block copolymer of PEO-PPO-ethylenadiamine, copolymer of PNIPAAm and acrylic acid (AAc), and P(NIPAAm-co-AAc). These solutions have a lower critical solution temperature (LCST), and their viscosity increase while heated above LCST.
The disclosed solutions in this invention normally contain a major amount of water (preferably purified water, physiological saline, or the like) in addition to the sclerosant and thickener. The compositions can also be lyophilized. Minor amounts of other ingredients such as pH adjusters (e.g., a base such as NaOH), anesthetic agent, buffering agents, and preservatives may also be present depending upon the route of administration and the preparation desired. The compositions can also be isotonic (i.e., it can have the same osmotic pressure as blood).
An aspect of the present invention encompasses an anesthetic to decrease the pain or discomfort associated with injection the compound. Example of anesthetics include but are not limited to lidocaine, xylocaln, novocain, benzocain, prilocaln, ripivacain, propofol, benzyl alcohol, and chlorobutanol. Typically the anesthetic will be used with aqueous base and thus will be mixed with sclerosant/thickener compound prior to administration. A suitable concentration of the anesthetic will be from 0.01% to 6% based on the total weight and the agent selected.
Alternatively, the pH of the sclerosing agent can be modified through a buffer system during the preparation to equal (or close to) the human physiologic pH value. It is believed that the pain the patients feel during injection of sclerosing agent is mainly due to the non-physiologic pH value of the agents. A buffering agent is a chemical compound or compounds that are added to the solution to allow that solution to resist changes in pH as a result of either dilution or small addition of acid or base. A buffering agent can be added in the sclerosant/thickener to adjust the pH value of the compound. Example of buffers are dibasic and monobasic phosphates, citrates, disodium phosphate, sodium diphosphate, disodium hydrogen phosphate and sodium dihydrogen phosphate, sodium phosphate, secondary sodium phosphate, sodium carbonate, phospate buffered saline (PBS), Tris-HCl, citrate-phosphate, Tricine, Hepes and maleate or the salt of weak organic acid with a strong base. The buffering agent, if present, may typically be present in the activated form in a concentration of about 0-4% of the compound. Alternatively, a contrast agent can be added in the carrier for enhanced Fluoroscopy visibility. If desired, isotonicity of this invention may be accomplished using sodium chloride, or other pharmaceutically acceptable agents such as dextrose, boric acid, sodium tartrate, propylene glycol or other inorganic or organic solutes.
A pharmaceutically acceptable preservative can be employed to increase the shelf-life of the compositions. Benzyl alcohol may be suitable, although a variety of preservatives including, for example, parabens, thimerosal, chlorobutanol, or benzalkonium chloride may also be employed. A suitable concentration of the preservative will be from 0.02% to 2% based on the total weight and the agent selected.
After the sclerosant/thickener is injected into the vessel and forms a plug, the sclerosant will be released from the sclerosant/thickener compound in two ways: dissolving and diffusion. First, the thickener begins to draw water from the surroundings and dissolved in the blood at the interface between the blood and the sclerosant/thickener. The sclerosant in the thickener is then released as the thickener dissolves in the blood which is a zero-order process. As a result, the vessel wall is sclerosed starting at the ends of the treated vessel segment and slowly moves to the middle as the sclerosant/thickener dissolving. The sclerosant/thickener dissolving rate is determined by the molecular weight of the thickener, sclerosant/thickener interaction, the type of sclerosant, and additive used, etc. A study done by B. C. Anderson, et al. (2001) indicates that the rate of Pluronic F127 dissolution controls the drug release for hydrophobic small molecular weight drugs.
The second mechanism for the release of sclerosant from the thickener is diffusion. The sclerosant diffuses into the vessel wall at the sclerosant/thickener and vessel wall interface. A study done by S. Mallapragada (1999) indicated that about 70-80% of the drug is released by the diffusion in Pluronic. This is especially true for small size non-surfactant sclerosants. They can easily diffuse into the vessel wall before the sclerosant/thickener is dissolved in the blood. As a result, the sclerosing rate in the vessel wall is controlled by both the sclerosant/thickener dissolving and sclerosant diffusion rates in the thickener.
Some studies were done on the parameters to affect the drug release rate in Pluronic hydrogel. Increasing Pluronic F127 concentration in the gel decreases gel dissolution and drug release rates. The drug release rate was zero-order with either hydrophilic or hydrophobic drugs, and it can also be controlled by the additive in the Pluronic. T. Moore, et al. (2000) studied the dissolution of Pluronic F127 under stirred conditions. The addition of the inorganic salt can increase the bulk viscosity of the gel, however it has no significant effect in the dissolution rate or drug release rate. A study done by Desai et al. (1998) found that additional PEG and PVP increase the dissolving and drug release rate of Pluronic F127 (or PF127). On the other hand, methylcellulose (MC) and hydroxypropyl methylcellulose (HPMC) reduce the dissolving and drug release rate of Pluronic. L. Zhang, et al. (2002) found polyvinyl pyrrolidone (PVP), carboxy methylcellulose (CMC) decreased the release rate of ceftiofur in the Poloxamer 407 gel. As a result, the drug release rate and dissolving rate of sclerosant/thickener can be controlled depending on the concentration, additive and composition of the thickener used.
The invention disclosed herein may be used to treat vascular diseases such as hemorrhoids, venous insufficiencies, varicose vein, esophageal varices, venous-drainage-impotence of the penis, vascular malformation, and to stop excessive blood supplied to tumors. In these treatments, the injectable sclerosant/thickener compound is typically introduced into the vessel to be treated by subcutaneous needle injection or by a catheter. For the treatment of venous insufficiencies, the target injection site is superficial veins. The injected sclerosant/thickener compound replaces the blood in the vessel and cause irreversible endothelial injury in the target vein without causing any adverse effects. This causes a localized inflammatory reaction and produces small thrombosis that eventually results in permanent fibrosis and elimination of the vessel.
The injectable sclerosant/thickener compound disclosed herein can be in a ready for use prefilled sterile syringe. Or, it can be provided in a vial in the form of sclerosant/thickener solution. In these embodiments, the end user could add water or other pharmaceutically acceptable carrier and/or additional components prior to injection. Alternatively it can be in a two compartments pre-filled syringe, wherein one compartment contains a sclerosant/thickener compound and the other compartment contains a pharmaceutically acceptable curing or cross linking agent such as CaCl2 solution if Agnate is used as thickener. Once the sclerosant/thickener compound has been prepared by any one of the existing processes, it can be applied by subcutaneous injection into the vessels to be treated. The compound disclosed herein may be optionally be sterilized by Gamma or E-beam irradiation, filtering, heating or exposure to ethylene oxide gas.
Several other methods can also be used to introduce the new compound in the target vessel. In one embodiment of the invention, sclerosant is mixed with a thickening agent. The solution is injected into the blood vessel through a needle or a catheter. The viscosity of the sclerosant/thickener is higher than the blood and form a plug in the blood vessel. The examples of this embodiment are cellulose and cellulose derivatives.
In another embodiment of this invention, a biocompatible hydrogel is used as thickener. It is mixed with a sclerosant, and then the sclerosant/thickener compound is injected into vessel by either a needle or a catheter. The example of this embodiment is PVP, gelatin and PEO-PPO-PEO copolymers.
In another embodiment of this invention, sclerosant is mixed with one of the polymer components before polymerization, gelling or crosslinking. The sclerosant/polymer component and the other polymer component (or catalyst, crosslinking agent, etc.) are introduced to the same vessel either with the same needle or from a separate needle or catheter. The sclerosant/polymer components are controlled to meet and polymerize (or gel or crosslink) at the target site of the vessel. The viscosity of the sclerosant/polymer increases, and the solubility of the sclerosant decreases significantly after the polymerization (or gel or crosslink). The example of this embodiment is Alginate. The Alginate solution can be mixed with a sclerosant (without causing gelling) and be injected into the vessel with a needle or a catheter. Ca+2 solution is a typical crosslinking agent for Alginate. It can be injected into the target vessel with a needle or a catheter to mix with the Alginate/sclerosant solution and form a gel in the vessel. The sclerosant is then released into the vessel wall through diffusion and as Alginate is resorbed into the blood. It is also part of this invention if the sclerosant is mixed with the Ca+2 and then injected into the vessel to mix with Alginate, which is injected separately.
In another embodiment of this invention, sclerosant is mixed with one of the polymer components. The sclerosant/polymer component and the other polymer component are introduced to the same vessel from separate lumen of a multi-lumens needle or catheter. They are controlled to meet and polymerize (or gel or crosslink) at the target site of the vessel. The example of this embodiment is Alginate. The Alginate solution can be mixed with a sclerosant (without causing gelling) and be injected into the vessel through a lumen in a multi-lumens needle or catheter. Ca+2 solution can be injected into the target vessel through another lumen in a multi-lumens needle or catheter to mix with the Alginate/sclerosant solution and form a gel in the vessel. It is also part of this invention if the sclerosant is mixed with the Ca+2 and then injected into the vessel to mix with Alginate, which is injected through a different lumen.
In another embodiment of this invention, sclerosant is mixed with an environmentally sensitive hydrogel. The viscosity of the sclerosant/environmentally sensitive hydrogel increases significantly when it is injected into the blood vessel through a needle or a catheter. The solubility of the sclerosant decreases significantly after the gelling. The example of this embodiment is PEO-PPO-PEO block copolymer.
The following examples are included to demonstrate preferred embodiments of the invention (for intravenous administration of sterile sclerosant solutions). It should be appreciated by those of skill in the art that the materials disclosed in the examples represent materials to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a similar result without departing from the spirit and scope of the invention. The description is intended to illustrate the principles of the present invention and specific modes encompassed thereby.
The compositions of this invention are prepared by mixing the ingredients following generally accepted procedures. For example, 5 mg of STS (obtained from Aldrich) is dissolved in 100 ml of distilled water. 200 mg of Pluronic (F127, obtained from BASF) is added into the solution in a blender at room temperature to assist the mixing. After the mixing with Pluronic, 10 mg Xylocaln (obtained from Aldrich), 2 mg Benzalkonium chloride (obtained from Aldrich), and 6 mg disodium phosphate were added into the solution with appropriate mixing in the blender. Finally, the pH adjusters, 0.3 mg NaOH (obtained from Aldrich), is introduced into the solution to retain the desired pH (7.3). The sterility of the solution is ensured by filtering the solution through a standard 0.3 μm filter with a syringe. Instead of the final concentration, a concentrated mixture may be prepared and adjusted to the final concentration and viscosity by the addition of water or a buffer before injection. Compositions can be administered in dosages and by techniques well known to those skilled in the medical arts and the delivery method used for administration (e.g., needle vs. catheter).
