HK1151964A - Single vial formulation for medical grade cyanoacrylate - Google Patents

Description

Single vial formulation of medical grade cyanoacrylate

Reference to related applications

This application claims priority from U.S. provisional application No. 60/987,349 entitled "single vial formulation of medical grade cyanoacrylate" filed on 12.11.2007.

Background

Technical Field

The invention relates to storage-stable cyanoacrylates which can be used for embolizing vascular aneurysms or for sealing body spaces or cavities, wherein alkyl cyanoacrylates having an alkyl chain containing more than 4 alkyl carbon atoms are used. The invention also relates to a single vial formulation of a cyanoacrylate useful in vivo, and to a method of preparing a cyanoacrylate monomer suitable for use in such a single vial formulation.

Description of the related Art

Cerebral aneurysms are balloon-like swellings of the vessel walls in the brain. Weakening of the cerebral vessel wall often causes rupture, bleeding and death. Cerebral aneurysms are more common in people over the age of 65 and may occur in up to 5% of the population. Smoking and hypertension appear to significantly increase the likelihood of a human suffering from a cerebral aneurysm. It is estimated that about 30,000 people are diagnosed with cerebral aneurysms annually in the united states. However, it is estimated that 450 million people in the united states suffer from asymptomatic, undiagnosed cerebral aneurysms. It is expected that this segment of the population will increase as the population ages.

Aneurysms can be treated by direct (cranial) surgery or by intravascular methods. Direct surgery is performed under general anesthesia by opening the skull and determining the neck of the aneurysm. Which is the junction of a normal blood vessel with a weakened dilated aneurysm. Clips are placed across this area if possible. This procedure involves a lengthy cranial procedure requiring several days of hospitalization.

Endovascular surgery is also performed under general anesthesia by navigating a small tube or catheter under X-ray guidance from a blood vessel in the leg artery into the aneurysm. The aneurysm was filled with tiny platinum loops. The patient is selected according to the individual patient and the aneurysm anatomy. The endovascular loop placement procedure requires up to 3-5 hours and requires multiple loops of 6-12 to be placed.

With the advent of the compositions and methods disclosed herein, embolization using cyanoacrylate compositions represents a practical alternative to placing titanium rings, requiring less surgical time and producing better results.

U.S. patent No.6,037,366, incorporated herein in its entirety, discloses cyanoacrylate compositions which include mixing of two separate components for immediate administration.

Component I consists of cyanoacrylate liquid monomers containing pure phosphoric acid (250ppm), hydroquinone (100ppm) and 4-methoxyphenol (1200 ppm). The composition is stable and unchanged within two years. Although stable for long term storage, the container in which component I is stored also requires cleaning and preparation to achieve such stability. The liquid monomer used in component I is preferably 2-hexyl cyanoacrylate.

The component II consists of pure gold powder, a small amount of partial polymer of the same cyanoacrylate and a plasticizer. The preferred plasticizer is ethyl myristate, but any liquid long chain fatty acid ester can work in this formulation. This patent discloses that some polymers of cyanoacrylates are unstable and change their structure and properties even in the solid state. Furthermore, the patent discloses that such a change is an exponential change and that the polymer must be used for a limited time before deterioration occurs.

U.S. patent No.6,476,069, incorporated herein in its entirety, discloses cyanoacrylate compositions prepared and stored as a monomer component and a second component. The two components are mixed at the time of use.

The monomer component can be an alkyl cyanoacrylate and at least one polymerization inhibitor. Examples of the disclosed monomer components consist of cyanoacrylate monomers and at least one polymerization inhibitor. In one example the monomer component consists of 2-hexyl cyanoacrylate, hydroquinone, 4-methoxyphenol and phosphoric acid.

The second component can be a composition that: which includes contrast materials such as gold, platinum, tantalum, titanium, tungsten, and barium sulfate, etc., mixed with an alkyl cyanoacrylate polymer material and an esterified fatty acid such as ethyl myristate. The monomer component and the second component are packaged separately and used as an embolic agent immediately after mixing.

U.S. patent No.6,476,070, incorporated herein in its entirety, discloses an invention called Neuracryl M, wherein Neuracryl M1 corresponds to the monomeric component and Neuracryl M2 corresponds to the second component consisting of gold-coated 2-hexyl acrylate. Neuracyl M is a two-part embolic agent consisting of a glass ampoule containing 1.25ml of Neuracyl M1 and a rubber stopper glass vial containing Neuracyl M2 (a mixture of 2-hexyl cyanoacrylate, esterified fatty acids and gold particles). Before use, the contents of the vial of Neuracryl M1 were injected into the vial containing Neuracryl M2, and the two parts were shaken thoroughly together until mixed. Gold particles and esterified fatty acids are used to block polymerization and provide visualization. To avoid separation or contamination of the components, the two parts are mixed and used immediately.

U.S. patent No. re39,150, incorporated herein in its entirety, discloses compositions which are cyanoacrylates comprising mixing the contents of two separate containers for immediate administration. The composition may comprise 7 ingredients which are divided into two parts before mixing and use.

The embolic agent disclosed in the above patent requires two vials of the formulation. The contents of the two vials are combined to form an embolic agent for immediate clinical use. The suppository formed from the two-vial formulation must be used immediately. In addition, compositions of fully polymeric materials (including cyanoacrylates) dissolved in solvents have been proposed for use in embolotherapy. These solutions rely on the dispersion of a solvent (e.g., DMSO) after injection to precipitate the polymer at the site of use. Mixing at the point of use typically takes about 30 minutes. The patient receives a considerable dose of solvent (and the attendant risks) and the precipitation process is not sufficiently controllable, nor is the precipitation product satisfactory.

We have developed compositions and methods relating to polymerizable cyanoacrylate agents for vascular embolization and other related uses, having in at least certain embodiments one or more of the following desirable properties: moderate cohesion, strong rubber casting, development, good body tolerance and/or the ability to be produced and packaged in a single vial formulation that is storage stable.

Summary of The Invention

One embodiment of the present disclosure includes a medical grade composition suitable for application to or in the human body comprising (a) a polymerizable alkyl cyanoacrylate monomer or oligomer; (b) at least one polymerization inhibitor; (c) a contrast agent; and (d) a plasticizer, wherein the composition is sealed in a single container, stable for more than one month at room temperature and suitable for polymerization in vivo.

One embodiment of the present disclosure includes a method of preparing a cyanoacrylate monomer of formula (I)

Wherein R is an alkyl group of 4 to 10 carbon atoms, comprising:

(a) reacting formaldehyde with a compound of formula (1-A) in the presence of a catalyst,

to provide a partial polymer of an alkyl cyanoacrylate, wherein R is as defined above for formula I;

(b) adding a compound selected from the group consisting of 4-methoxyphenol, 2, 6-di-tert-butyl-4-methylphenol, SO to a portion of the polymer of alkyl cyanoacrylate₂And any combination thereof;

(c) containing a compound selected from 4-methoxyphenol, 2, 6-di-tert-butyl-4-methylphenol, SO₂Cracking a portion of the polymer of the alkyl cyanoacrylate in a vessel of a second polymerization inhibitor, and any combination thereof, to provide a cracked alkyl cyanoacrylate;

(d) containing a compound selected from 4-methoxyphenol, 2, 6-di-tert-butyl-4-methylphenol, SO₂Distilling the cracked alkyl cyanoacrylate in (c) in a vessel of a third polymerization inhibitor, and any combination thereof, to provide an alkyl cyanoacrylate monomer fraction; and

(e) the third polymerization inhibitor is removed from the alkyl cyanoacrylate monomer fraction.

One embodiment of the present disclosure includes a method of preparing a medical grade alkyl cyanoacrylate composition in a single container, the method comprising (a) photochemically treating an alkyl cyanoacrylate monomer to provide an alkyl cyanoacrylate oligomer having a viscosity of from about 5 to about 1000 centipoise; and (b) combining the alkyl cyanoacrylate oligomer with a plasticizer solution comprising a plasticizer and a polymerization inhibitor to provide an alkyl cyanoacrylate oligomer plasticizer mixture.

One embodiment of the present disclosure includes a method of providing a single container of an alkyl cyanoacrylate formulation, the method comprising:

(a) providing an alkyl cyanoacrylate oligomer formed by partially polymerizing monomers by irradiating the monomers of formula (I);

wherein R is an alkyl group of 4 to 10 carbon atoms,

wherein the alkyl cyanoacrylate monomer of formula (I) has a viscosity of from about 3 centipoise to about 5 centipoise; and

the alkyl cyanoacrylate oligomer has a viscosity of from about 10 centipoise to about 1000 centipoise;

(b) combining an alkyl cyanoacrylate oligomer with a plasticizer and a polymerization inhibitor to provide an alkyl cyanoacrylate oligomer plasticizer mixture; and

(c) the resulting alkyl cyanoacrylate oligomer plasticizer mixture is placed in a single container, and the resulting single container alkyl cyanoacrylate formulation is stable for more than one month at room temperature and is suitable for polymerization in vivo.

One embodiment of the present disclosure includes a composition comprising:

(a) alkyl cyanoacrylate oligomers;

(b) at least one polymerization inhibitor;

(c) a contrast agent; and

(d) plasticizer

Wherein the alkyl cyanoacrylate oligomer has been prepared from an alkyl cyanoacrylate monomer;

wherein the composition is stable for more than one month in a single container, and

when the composition is exposed to an anionic environment it polymerizes to form a polymeric structure.

One embodiment of the present disclosure includes a composition comprising:

(a) an alkyl cyanoacrylate oligomer, wherein 30% to 50% by weight of the composition is said alkyl cyanoacrylate oligomer, wherein the alkyl cyanoacrylate oligomer has a viscosity of about 15 centipoise to about 500 centipoise

(b) A plasticizer mixture, wherein 10% to 30% by weight of the composition is the plasticizer mixture

(c) A contrast agent, wherein 30% to 50% by weight of the composition is said contrast agent

Wherein the composition is in a single container and is stable for more than one month.

One embodiment of the present disclosure includes a method of making an embolic agent comprising

(a) Mixing an alkyl cyanoacrylate and a plasticizer solution to provide an alkyl cyanoacrylate oligomer plasticizer solution

(b) Mixing the alkyl cyanoacrylate oligomer plasticizer solution and contrast agent in a single container to provide a pre-sterilized mixture

(c) Storing the pre-sterilized mixture under an inert atmosphere

(d) Heating a single container containing the pre-sterilization mixture to a temperature sufficient to sterilize the pre-sterilization mixture

Wherein the alkyl cyanoacrylate oligomer has a viscosity of from about 15 centipoise to about 500 centipoise; and is

The embolic agent is stable for more than one month.

One embodiment of the present disclosure includes a formulation for remodeling a body space, the formulation comprising:

alkyl cyanoacrylate in an amount up to about 50 weight percent;

a plasticizer mixture in an amount up to about 30 weight percent, wherein the plasticizer mixture consists of acyl trialkyl citrate, 4-methoxyphenol, 2, 6-di-tert-butyl-4-methylphenol, sulfur dioxide, and mixtures thereof; and

a contrast agent in an amount up to 50 weight percent, wherein the contrast agent is selected from the group consisting of gold, platinum, tantalum, titanium, tungsten, and barium sulfate; and is

The formulation is chemically and physically stable in a single vial for at least 30 days at room temperature.

One embodiment of the present disclosure includes a kit for embolizing a body cavity, the kit comprising, in a single container, a formulation for remodeling a body space and a catheter or syringe configured for introducing an embolization treatment product into the body cavity, wherein the kit includes written instructions or information.

Description of The Preferred Embodiment

Although alkyl cyanoacrylates have been proposed in the past for embolization of aneurysms and for filling other spaces in the body, these early research efforts have not led to the availability of such products and methods for general clinical treatment. This is due in part to formulation deficiencies including the need to mix the two components on site prior to use or the need to inject large amounts of solvent-dissolved cyanoacrylate polymer. Contrary to expectations and general knowledge in the prior art, we have found that medically useful polymerizable alkyl cyanoacrylate formulations can be prepared and stored in a single bottle for more than 1 month. Certain embodiments of the present invention provide compositions comprising a single vial formulation of at least one oligomer of an alkyl cyanoacrylate monomer, at least one polymerization inhibitor, a contrast agent, and a plasticizer.

In certain embodiments, the oligomer component can be one or more alkyl cyanoacrylate oligomers and at least one polymerization inhibitor. In a preferred embodiment, the oligomer component can be n-hexyl cyanoacrylate. In a preferred embodiment, the composition can include multiple (e.g., three) polymerization inhibitors, for example, the polymerization inhibitors can be hydroquinone, 4-methoxyphenol, and phosphoric acid. In a typical embodiment, the polymerization inhibitor can be 2, 6-bisTert-butyl-4-methylphenol, 4-methoxyphenol and sulfur dioxide (SO)₂)。

Certain embodiments can comprise a method of purifying an alkyl cyanoacrylate monomer to its crystalline form. In certain embodiments, the method of purifying an alkyl cyanoacrylate is capable of providing an alkyl cyanoacrylate monomer of about 95% or greater purity. In preferred embodiments, the alkyl cyanoacrylate has a purity of about 97% or greater. In a more preferred embodiment, the alkyl cyanoacrylate has a purity of about 98% or greater. In a particularly preferred embodiment, the alkyl cyanoacrylate is at least 99% pure.

Certain embodiments comprise substantially pure alkyl cyanoacrylate monomers or oligomers. For example, the alkyl cyanoacrylate monomer can be methyl cyanoacrylate, n-butyl cyanoacrylate, isobutyl cyanoacrylate, n-hexyl cyanoacrylate, 2-hexyl cyanoacrylate, or 2-octyl cyanoacrylate which is purified to about 95% or greater purity. In a preferred embodiment, methyl cyanoacrylate, n-butyl cyanoacrylate, isobutyl cyanoacrylate, n-hexyl cyanoacrylate, 2-hexyl cyanoacrylate or 2-octyl cyanoacrylate can be purified to a purity of 97% or more. In a more preferred embodiment, methyl cyanoacrylate, n-butyl cyanoacrylate, isobutyl cyanoacrylate, n-hexyl cyanoacrylate, 2-hexyl cyanoacrylate, or 2-octyl cyanoacrylate can be purified to 98% or greater purity. In a most preferred embodiment, methyl cyanoacrylate, n-butyl cyanoacrylate, isobutyl cyanoacrylate, n-hexyl cyanoacrylate, 2-hexyl cyanoacrylate, or 2-octyl cyanoacrylate can be purified to a purity of 99% or greater. In certain aspects, the alkyl cyanoacrylate monomer can be isolated in its crystalline form.

The stability of formulations prepared from alkyl cyanoacrylate monomers can be related to the purity of the monomers used. These properties can include, but are not limited to, polymerization rate and stability during storage of the monomer. One advantage of substantially pure alkyl cyanoacrylates can be that compositions incorporating substantially pure alkyl cyanoacrylates can require smaller amounts of additives, such as polymerization inhibitors, stabilizers, and the like, to achieve the desired results, which would otherwise require larger amounts of the same additives. One benefit of this advantage is that less raw material can be used, thereby saving costs. Another benefit can be that the composition will contain a lower amount of additives. This can be the desired result of any composition that is subject to approval by the U.S. food and drug administration or similar regulatory agency prior to sale. Of paramount importance is the ability of the product to form a storage stable formulation.

It is believed that the prior art fails to provide single vial formulations of alkyl cyanoacrylates, particularly formulations comprising alkyl cyanoacrylate monomers having 4, 5, 6 or more carbon atoms in the alkyl chain (or oligomers in certain embodiments to date), due to the stability of the alkyl cyanoacrylate monomer. Accordingly, certain aspects of the present invention provide suitably pure monomers as well as single vial formulations comprising or made from oligomers of the monomers.

Certain embodiments include compositions having partially polymerized cyanoacrylate oligomers therein. We have found that partial polymerization of alkyl cyanoacrylates using uv light results in an advantageous product profile with extended shelf life that is particularly suitable for single vial formulations.

Certain embodiments can provide alkyl cyanoacrylates whose polymerization rate can be predicted, and compositions of unreacted monomers ("prepolymers") are more stable. One of ordinary skill in the art can select monomers having suitable polymerization properties for the desired use or to formulate a monomer composition having desirable polymerization properties. Previously, substantially pure alkyl cyanoacrylates (particularly those having carbon chains of 4, 5, 6 or more carbon atoms) have not been obtained due to the difficulty of purification using conventional chemical methods. Furthermore, most of these methods involve conditions that lead to degradation or spontaneous polymerization of the alkyl cyanoacrylate. Heretofore, such substantially pure alkyl cyanoacrylate monomers having the desired chain length (e.g., alkyl groups of 4, 5 and especially 6 carbons) have not been generally available.

Another embodiment of the invention can provide a method of filling, closing, partially filling, or partially closing an unfilled volume or space within a body. The use of the disclosed compositions as embolizing agents for filling vascular aneurysms is particularly preferred.

Definition of

The term "alkyl cyanoacrylate" as used herein refers to a viscous compound or mixture of compounds based on cyanoacrylate monomers of formula I:

wherein R is selected from alkyl groups of 1 to 16 carbon atoms. Also part of the polymers (i.e. oligomers) of these cyanoacrylates are covered in this definition. Preferred arylalkyl groups are 4 to 8 carbon atoms and include, for example, methyl, ethyl, n-butyl, isobutyl, pentyl, n-hexyl, 2-hexyl, n-heptyl, 2-heptyl, n-octyl and 2-octyl. More preferably, R is n-hexyl, 2-hexyl, isobutyl, 2-heptyl and 2-octyl, most preferably R is n-hexyl.

The term "partial polymer" or "oligomer" as used herein means a polymer consisting of only a few monomer units, such as dimers, trimers, tetramers, etc., or mixtures thereof. The average number of monomers in the partial polymer can generally be up to about 10, or, if continued polymerization is permitted, the number of monomer units can advantageously be between 10 and 100. "partial polymers" or "oligomers" can be further polymerized to form polymers.

The term "polymer" as used herein means a substance composed of large molecular weight molecules composed of repeating structural units or monomers. "Polymer" is defined as generally being under the limits of polymerization in the particular formulation in which polymerization occurs so that polymerization is substantially complete. This is in contrast to "partial polymers" or "oligomers" which can be prepared by partial polymerization of the composition, such that substantially further polymerization is possible.

The term "alkyl" as used herein refers to a carbon chain having 1 to 16 carbon atoms, wherein the carbon atoms may be straight or branched.

The term "lower alkyl" as used herein refers to a carbon chain having 1 to 8 carbon atoms, wherein the carbon atoms may be straight or branched. Examples of lower alkyl groups include, but are not limited to, methyl, ethyl, n-butyl, isobutyl, pentyl, n-hexyl, 2-hexyl, n-heptyl, 2-heptyl, n-octyl and 2-octyl.

The term "branched alkyl" as used herein refers to a carbon chain having 1 to 16 carbon atoms, wherein the carbon chain contains at least one secondary or tertiary substituted carbon atom.

The term "branched lower alkyl" as used herein refers to a carbon chain having from 1 to 8 carbon atoms, wherein the carbon chain contains at least one secondary or tertiary substituted carbon atom, such as 2-hexyl, isobutyl, 2-heptyl, and 2-octyl.

The term "biocompatible plasticizer" as used herein refers to any material that is soluble or dispersible in the alkyl cyanoacrylate that increases the flexibility of the resulting polymeric coating on the skin surface and is compatible with the skin as measured by the absence of skin irritation. Suitable plasticizers are well known in the art and include those disclosed in U.S. Pat. Nos.2,784,127 and 4,444,933, the disclosures of both of which are incorporated herein by reference in their entirety. Specific plasticizers include, by way of example only, butyl benzyl phthalate, dibutyl phthalate, diethyl phthalate, dimethyl phthalate, dioctyl phthalate, trialkyl acylcitrates, benzoates of branched aliphatic compounds of dihydroxy and polyhydroxy, tricresyl phosphate, and the like. The plasticizer used is advantageously selected to avoid skin irritation. Preferred plasticizers for use in the present invention are acyl trialkyl citrates wherein each alkyl group independently contains from 1 to 10 carbon atoms. For example, alkyl acylcitrates include, but are not limited to, trimethyl O-acetyl citrate, triethyl O-acetyl citrate, tri-n-propyl O-acetyl citrate, tri-n-butyl O-acetyl citrate, tri-n-pentyl O-acetyl citrate, tri-n-hexyl O-acetyl citrate, trimethyl O-propionyl citrate, triethyl O-propionyl citrate, tri-n-propyl O-propionyl citrate, tri-n-butyl O-propionyl citrate, tri-n-pentyl O-propionyl citrate, tri-n-hexyl O-propionyl citrate, trimethyl O-butyryl citrate, triethyl O-butyryl citrate, tri-n-propyl O-butyryl citrate, tri-n-butyl O-butyryl citrate, tri-n-pentyl O-butyryl citrate, tri-n-hexyl O-butyryl citrate, and the like. A typical plasticizer is O-acetyl tri-n-butyl citrate.

The term "anionic environment" as used herein means having a free anion, e.g. OH^-The environment of (2). Anions in water or other aqueous media, such as blood, are capable of catalyzing the polymerization of cyanoacrylates.

The term "adhesion" or "tacky" as used herein refers to the property or tendency of one material to be attracted to the surface of a second material. Adhesion occurs as a result of the interaction between the two materials. Whether adhesion occurs or not depends on the nature of the second material relative to the first material.

The term "cohesive" or "cohesive" as used herein refers to the property or tendency of a material to adhere to itself. For example, this property is manifested in the material or composition remaining intact as a single mass when introduced into a stationary fluid or a moving stream of liquid, such as blood. The lack of cohesive integrity results in the composition breaking down into a plurality of smaller subunits.

The term "microparticles" as used herein refers to small particles of 200 mesh (0.075mm) or smaller, preferably 400 mesh or smaller.

The term "alkyl esterified fatty acid" as used herein means that the fatty acid is derivatized to form an ester functional group having an alkyl group, such as ethyl myristate. These compounds are formed to have alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl; and carboxylic acids having alkyl side chains from 1 carbon, i.e., acetic acid, to 17 carbon atoms in length, such as propionic, butyric, isobutyric, valeric, isovaleric, pivalic, lauric, myristic, palmitic, and stearic acids.

The term "contrast agent" as used herein is a compound or composition that selectively absorbs or deflects radiation such that the material is visible under X-ray or other types of imaging such as MRI and ultrasound. X-ray contrast agents typically include iodized and brominated oils, as well as commercially available compositions such as Pantopaque, Lipiodol, and Ethiodol. These commercially available compositions act as contrast agents, also diluting the amount of liquid monomer, thereby slowing the rate of polymerization. In addition, certain metals, such as gold, platinum, tantalum, titanium, tungsten, and barium sulfate, among others, have properties that enable them to function as contrast agents. These contrast agents, in particular metals, preferably have a smooth, regular morphology, preferably a spherical morphology. This can improve the viscosity and flowability of the final product.

The term "polymerization" as used herein refers to a chemical process by which a monomeric unit or a portion of a polymeric unit chemically reacts with other monomeric units or a portion of a polymeric unit to form larger aggregates comprising the monomeric unit or the portion of the polymeric unit.

The term "complete polymerization" as used herein refers to a chemical process in which a monomer unit, a partial polymer unit, or an oligomer undergoes a chemical reaction to form a polymer that does not undergo significant additional chain extension polymerization.

The term "polymer" as used herein means a substance composed of large molecular weight molecules composed of repeating structural units or monomers linked by covalent chemical bonds.

The term "partial polymer" as used herein refers to a substance composed of repeating structural units or monomers linked by covalent chemical bonds that is capable of undergoing further chain-extension polymerization to form a polymer.

The term "space" as used herein refers to an unfilled volume or cavity within a patient.

The term "stability" as used herein refers to the ability of a compound or formulation to resist degradation or polymerization after manufacture and prior to use.

The term "polymerization inhibitor" as used herein refers to an agent that stabilizes the alkyl cyanoacrylate monomer or single vial formulation by inhibiting polymerization. In the context of the present invention, the term refers to one or more property (inrinsic) agents that stabilize and inhibit polymerization by at least one mechanism. By varying the amount of one or more polymerization inhibitors, the rate of polymerization can be controlled. Polymerization inhibitors have different modes of activity, for example, hydroquinone acts mainly to inhibit high-energy free radicals; 4-methoxyphenol is mainly used for inhibiting low-energy free radicals; and, phosphoric acid affects the rate of anionic polymerization.

In certain embodiments, the composition can be formed from alkyl cyanoacrylate monomer and/or oligomer units, such as methyl cyanoacrylate, n-butyl cyanoacrylate, isobutyl cyanoacrylate, n-hexyl cyanoacrylate, and 2-hexyl cyanoacrylate, with at least one polymerization inhibitor, such as hydroquinone, 4-methoxyphenol, and phosphoric acid. In a preferred embodiment, the composition is capable of forming a polymer when contacted with an anionic environment, such as blood or tissue.

The compositions of the present invention can advantageously have several or all of the following properties.

1) The composition can be prepared and maintained in a single vial combination of polymerizable component and contrast agent for an appreciable length of time.

2) The compositions have the ability to reliably and predictably transition from a liquid state to a solid state in vivo.

3) The composition has a sufficiently low viscosity to be capable of being administered by a syringe, catheter, cannula, hose or other similar device.

4) The composition has cohesive properties such that when the composition is administered into an aqueous fluid environment, such as blood, the composition forms a single polymeric structure (including a multiphase structure).

5) The rate of heat release during polymerization of the composition is sufficiently low that the heat does not adversely affect surrounding tissues that may be heat sensitive.

6) The tissue toxicity and cytotoxicity of the composition and its biodegradation products are sufficiently low that it is well tolerated in vivo.

Cyanoacrylates are capable of generating heat when converted from a monomeric to an oligomeric or polymeric form. If the amount and rate of heat release are too great, the living tissue proximate the catheter can be adversely affected. In certain applications of this technology, control of the exotherm and exotherm rate during polymerization is important.

Preparation of the monomer component

The monomer component of the present invention is prepared as described in scheme a by forming the desired precursor ester from the corresponding alkyl alcohol and cyanoacetic acid, thereby yielding the desired alkyl cyanoacetate. Starting materials for this reaction are commercially available, for example from Sigma-Aldrich chemical, VWR, Fisher, Lancaster or Fluka chemical, or can be prepared according to procedures known to those of ordinary skill in the art.

Scheme A

The compound of formula 2 can be any alkyl alcohol wherein R has 1 to 16 carbon atoms, including but not limited to alkyl-based alcohols such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, and hexadecyl, wherein the above groups are linear (e.g., n-propyl, n-butyl, n-pentyl, or n-hexyl) or variously branched, such as sec-butyl, isobutyl, tert-butyl, isopropyl, 2-butyl, 2-pentyl, 2-hexyl, 2-heptyl, 2-octyl, and the like. Particularly advantageous alcohols are those disclosed in U.S. patent No.3,728,375 entitled "cyanoacrylate adhesive compositions," which is incorporated herein in its entirety. Particularly preferred alcohols may be selected from methanol, n-butanol, isobutanol, n-hexanol and 2-hexanol.

In certain embodiments, about 1 molar equivalent of the compounds of formula I and formula II are combined in about 100 ml/molar equivalent of a solvent such as toluene. To this mixture can be added a catalytic amount (about 1.0X 10)^-4Molar equivalents) of p-toluenesulfonic acid. The mixture can be stirred and heated to reflux. This preparation method is desirable to obtain the desired alkyl cyanoacetate in a purity of about 95%. One of ordinary skill in the art can readily modify the experimental conditions without departing from the present invention. Aspects such as choice of solvent, reaction time, temperature and choice of reagents are well within the ability of those skilled in the art. If desired, the material can be further purified using multiple distillations and purification techniques and procedures known to those of ordinary skill in the art, such as aqueous extraction, distillation under reduced pressure, column chromatography, and the like. The alkyl cyanoacetate is preferably substantially free of impurities. In one embodiment, the cyanoacetate has a purity of about 95% to about 100%.

Preparation of alkyl cyanoacrylates

Starting from an alkyl cyanoacetate, the desired alkyl cyanoacrylate monomer component of the invention can be synthesized by reacting it in a Knoevengel-type reaction as depicted in scheme B.

Scheme B

In certain embodiments, about 1 molar equivalent of formaldehyde (formula 4) prepared from paraformaldehyde and piperidine (about 0.33 ml/molar equivalent) can be combined in a solvent such as methanol (about 166 ml/molar equivalent). To the mixture, about 1 molar equivalent of alkyl cyanoacetate (formula 3) can be added dropwise. The reaction mixture can be refluxed with stirring to obtain the alkyl cyanoacrylate. Alkyl cyanoacrylates can be converted to the monomeric form by cracking and distillation. The reaction mixture can be further treated with about 0.2 to 0.7 molar equivalents, preferably about 0.2 to 0.6 molar equivalents, of phosphorus pentoxide to give the desired purified alkyl cyanoacrylate. It is advisable to carefully carry out the purification step in order to prevent the compound of formula (5) from polymerizing. For this reason, the system can be treated with traces of sulfur dioxide, and the receiver bottle can be treated with 4-methoxyphenol. After the preliminary cracking and distillation, the desired alkyl cyanoacrylate can be further purified using multiple distillations or other purification techniques known to those of ordinary skill in the art, such as distillation under reduced pressure, a rotating belt distillation column, and the like.

In a preferred embodiment, purified alkyl cyanoacrylates of formula I can be prepared using the following technique, wherein R is an alkyl group of 4 to 10 carbon atoms, preferably 5 to 10 or 5 to 8 carbon atoms, most preferably 6 carbon atoms:

the synthesis is designed to produce high purity alkyl cyanoacrylates that can be used to prepare single container (e.g., single vial) formulations of polymerizable alkyl cyanoacrylates for medical use. Care is taken to avoid contamination, polymerization and degradation of the product by maintaining the reaction mixture and product under a suitable non-reactive atmosphere or vacuum and by careful experimental methods.

One suitable synthetic scheme includes some or all of the following steps:

(a) paraformaldehyde particles, a catalytic amine, and a first solvent (e.g., methanol) are combined in a reaction vessel. For example, the catalytic amine can be a secondary amine, such as piperidine or diethylamine;

(b) heating and stirring the contents of the reaction vessel to obtain high quality formaldehyde (preferably at a temperature of about 65 ℃ to 80 ℃);

(c) reducing the amount of heat applied to the container (preferably to about 55 ℃);

(d) adding to a vessel a cyanoacetate compound of formula (1-a):

wherein R is as defined above for formula I;

(e) increasing the heat applied to the vessel to react the formaldehyde with the cyanoacetate to form alkyl cyanoacrylate (preferably at about 72 ℃ to about 78 ℃);

(f) removing the solvent (e.g., methanol) from the alkyl cyanoacrylate by distilling off 75% to 95% by volume of the liquid contained in the reaction vessel; the vessel and contents are then allowed to cool;

(g) after removing the first solvent, adding a second solvent (e.g., toluene) to the flask to form a mixture with the contents of the flask;

(h) distilling off about 85% to about 100% by volume of the solvent contained in the flask, including azeotropic distillation of the remaining first solvent and catalytic amine; the reaction vessel and contents were then allowed to cool;

(i) collecting an alkyl cyanoacrylate monomer of formula (I) as a distillate in a receiving flask containing a polymerization inhibitor such as 4-methoxyphenol, 2, 6-di-tert-butyl-4-methylphenol, hydroquinone or any combination thereof;

(j) placing the reaction vessel under vacuum, wherein the vacuum is preferably from about 5mmHg to about 0.1mmHg, more preferably from about 2mmHg to about 0.5 mmHg;

(k) heating the reaction flask to remove residual solvent by distillation under reduced pressure, preferably at a temperature below about 150 ℃;

(l) Stopping heating the reaction vessel, wherein the reaction vessel and contents are allowed to cool;

(m) breaking the vacuum using a non-reactive gas such as argon, nitrogen, sulfur dioxide, and combinations thereof;

(n) coating the reaction apparatus with SO₂。

(o) placing the reaction vessel under vacuum, wherein the vacuum is preferably from about 5mmHg to about 0.1mmHg, more preferably from about 2mmHg to about 0.5 mmHg;

(p) heating the reaction vessel to a temperature sufficiently high to vaporize the alkyl cyanoacrylate, wherein the temperature preferably does not exceed 200 ℃, and preferably is from about 170 ℃ to about 190 ℃;

(q) collecting the alkyl cyanoacrylate monomer of formula (I) as a distillate in a receiving flask containing a polymerization inhibitor such as 4-methoxyphenol, 2, 6-di-tert-butyl-4-methylphenol, hydroquinone, and any combination thereof;

(r) stopping heating;

(s) breaking the vacuum using non-reactive gases such as argon and nitrogen and combinations thereof;

(t) coating the reaction apparatus with SO₂；

(u) after collecting the distilled alkyl cyanoacrylate, removing the stabilizer using an inhibitor remover such as Aldrich 311332 to obtain an alkyl cyanoacrylate monomer of formula (I) having a viscosity of about 3 to about 8 centipoise, typically about 4 centipoise; and

(v) removal of SO by bubbling or sparging a non-reactive gas such as argon, nitrogen, or a combination thereof, into the alkyl cyanoacrylate₂。

In one embodiment, the alkyl cyanoacrylate monomer can be treated to form an alkyl cyanoacrylate oligomer that is more viscous than the alkyl cyanoacrylate monomer. For example, n-hexyl cyanoacrylate can be treated to form n-hexyl cyanoacrylate oligomers. Preferred oligomers are obtained by photochemical treatment of an alkyl cyanoacrylate monomer to form a mixture comprising a partially polymerized cyanoacrylate and having a higher viscosity than the alkyl cyanoacrylate monomer from which it is prepared. For example, the viscosity of the alkyl cyanoacrylate oligomer advantageously can be from about 10 centipoise to about 1000 centipoise, and the viscosity of the alkyl cyanoacrylate monomer forming the alkyl cyanoacrylate oligomer can be from about 2 centipoise to about 5 centipoise, as measured by a rheometer. The oligomer will typically have a viscosity of about 10 centipoise to about 50 centipoise.

In typical embodiments, a n-hexyl cyanoacrylate monomer having a viscosity of about 4 centipoise is treated to form a n-hexyl cyanoacrylate oligomer having a viscosity of about 15 centipoise to about 50 centipoise. In an exemplary embodiment, a n-hexyl cyanoacrylate monomer having a viscosity of about 4 centipoise can be processed to form a n-hexyl cyanoacrylate oligomer having a viscosity of about 25 centipoise to about 30 centipoise. In certain embodiments, the alkyl cyanoacrylate monomer can be photochemically treated to yield an alkyl cyanoacrylate oligomer. In typical embodiments, ultraviolet radiation can be used for photochemical treatment. In exemplary embodiments, the ultraviolet radiation can provide very controlled polymerization of the alkyl cyanoacrylate monomer to form alkyl cyanoacrylate oligomers that can be further polymerized. U.S. patent publication No. 20050197421, which is incorporated herein by reference in its entirety, discloses some methods of polymerizing cyanoacrylate monomers using radiation. In a typical embodiment, a n-hexyl cyanoacrylate monomer having a viscosity of about 4 centipoise can be treated with ultraviolet radiation to form a n-hexyl cyanoacrylate oligomer having a viscosity of about 15 centipoise to about 50 centipoise. In another exemplary embodiment, a n-hexyl cyanoacrylate monomer having a viscosity of about 4 centipoise can be treated with ultraviolet radiation to form a n-hexyl cyanoacrylate oligomer having a viscosity of about 25 centipoise to about 30 centipoise. In certain embodiments, the ultraviolet radiation source can be a mercury vapor lamp. In a typical embodiment, a 550 watt mercury vapor lamp in the photochemical reactor of Ace Glass Incorporated is used for the photochemical treatment.

Preparation

In certain embodiments, the alkyl cyanoacrylate components of the present invention are combined with at least one polymerization inhibitor. Typical inhibitors for alkyl cyanoacrylates can be, for example, hydroquinone, 4-methoxyphenol, pure phosphoric acid, 2, 6-di-tert-butyl-4-methylphenol, sulfur dioxide (SO)₂) Alkyl carboxylic acids, and the like. Mixtures of polymerization inhibitors are also contemplated. In a typical embodiment, 4-methoxyphenol, 2, 6-di-tert-butyl-4-methylphenol and sulfur dioxide (SO) can be used independently or in combination₂) Two or more of them.

Different polymerization inhibitors have different physical properties and thus alter the final properties of the composition. For example, hydroquinone can be used as a polymerization inhibitor for high-energy radicals; 4-methoxyphenol can be used as a low energy radical inhibitor and phosphoric acid can act to inhibit anionic polymerization and the rate of such polymerization.

The amount of inhibitor can be measured in parts per million of the alkyl cyanoacrylate. For n-hexyl cyanoacrylate, for example, the hydroquinone can be in the range of about 50 to about 500 Parts Per Million (PPM), the 4-methoxyphenol can be in the range of about 50 to about 500PPM, 2,6-di-tert-butyl-4-methylphenol can be in the range of about 50 to about 500PPM, SO₂Can be in the range of about 25 to about 300PPM and the phosphoric acid can be in the range of about 125 to about 375 PPM. In typical embodiments, the hydroquinone can be in the range of about 100 to about 350PPM, the 4-methoxyphenol can be in the range of about 100 to about 350PPM, the 2, 6-di-tert-butyl-4-methylphenol can be in the range of about 100 to about 350PPM, and the SO₂Can be in the range of about 50 to about 250PPM and the phosphoric acid can be in the range of about 185 to about 300 PPM. In more typical embodiments, the 4-methoxyphenol can be in the range of about 200 to about 300PPM, the 2, 6-di-tert-butyl-4-methylphenol can be in the range of about 200 to about 300PPM and the SO₂Can be in the range of about 75 to about 125 PPM.

In certain embodiments, the composition can include a contrast material, such as gold, platinum, tantalum, titanium, tungsten, barium sulfate, and the like; alkyl cyanoacrylate oligomer, and a plasticizer. Suitable contrast agents (opacifics or contrast agents) are further disclosed, for example, in U.S. patent publication No.20050287216, which is incorporated herein by reference in its entirety. In certain embodiments, the plasticizer can be butyl benzyl phthalate, dibutyl phthalate, diethyl phthalate, dimethyl phthalate, dioctyl phthalate, trialkyl acylcitrates, benzoates of dihydroxy and polyhydroxy branched chain aliphatic compounds, tricresyl phosphate, combinations thereof, and the like. In exemplary embodiments, the plasticizer can be an acyl trialkyl citrate, each alkyl group independently having from 1 to 10 carbon atoms. For example, the acylacylacylcitrate alkyl ester can be O-acetyl trimethyl citrate, O-acetyl triethyl citrate, O-acetyl tri-n-propyl citrate, O-acetyl tri-n-butyl citrate, O-acetyl tri-n-pentyl citrate, O-acetyl tri-n-hexyl citrate, O-propionyl trimethyl citrate, O-propionyl triethyl citrate, O-propionyl tri-n-propyl citrate, O-propionyl tri-n-butyl citrate, O-propionyl tri-n-pentyl citrate, O-propionyl tri-n-hexyl citrate, O-butyryl trimethyl citrate, O-butyryl triethyl citrate, O-butyryl tri-n-propyl citrate, O-butyryl tri-n-butyl citrate, O-butyryl tri-n-pentyl citrate, O-butyryl triethyl citrate, Tri-n-hexyl O-butyryl citrate, and the like. In typical embodiments, the plasticizer can be O-acetyl tri-n-butyl citrate.

In certain embodiments, the contrast agent is a particulate or nanoparticle of a liquid or solid contrast agent suspended in an alkyl cyanoacrylate. In typical embodiments, the contrast agent can be a solid contrast agent, such as gold, platinum, tantalum, titanium, tungsten, barium sulfate, and the like. In a more typical embodiment, the solid contrast agent can be gold suspended in an alkyl cyanoacrylate oligomer. For example, gold can be suspended in n-hexyl cyanoacrylate oligomer. Factors that affect the amount of contrast agent can include the amount of contrast agent necessary for fluoroscopy.

In certain embodiments, the sealed storage container can be heat sterilized according to methods such as those disclosed in Disinfection, Sterilization, and Preservation, Seymour S Block ed., Lippincott Williams & Wilkins, 2000, the entire contents of which are incorporated herein. For example, the sealed storage container can be heat sterilized at about 120 ℃ to about 190 ℃. In typical embodiments, the sealed storage container can be heat sterilized at 180 ℃ for about 3 minutes to about 15 minutes. In a more typical embodiment, the sealed storage container can be heat sterilized at 180 ℃ for about 4 minutes to about 6 minutes.

The prior art compositions comprising alkyl cyanoacrylate polymers typically use solvents or alkyl cyanoacrylate monomers to dissolve the alkyl cyanoacrylate polymers, and at least some of the compositions contemplated by the present invention do not contain significant amounts of solvents, particularly when alkyl cyanoacrylate oligomers, alkyl cyanoacrylate monomers, stabilizers, and contrast agents are excluded from the definition of solvent.

In certain embodiments, the composition includes an alkyl cyanoacrylate oligomer, a polymerization inhibitor, and a solvent-free contrast agent. In one embodiment, the amount of solvent can be less than about 10% w/w of the composition, typically the amount of solvent can be less than about 5% w/w of the composition, more typically the amount of solvent can be less than about 3%, 1% or 0.5% w/w of the composition.

In one embodiment, the composition is also largely free or substantially free of cyanoacrylate monomer (except for such monomer that may incidentally remain when the monomer is partially polymerized to produce oligomers). Alternatively, the amount of monomer may be sufficiently limited that it is insufficient to dissolve the cyanoacrylate polymer used as the viscosity modifier.

In certain embodiments, the alkyl cyanoacrylate formulations can be used to fill, block, partially fill, or partially block unfilled volumes or spaces ("voids") in a substance (mass). In particular, the composition is used to fill vascular aneurysms. The composition has the property of polymerizing when it is in contact with an aqueous environment, for example when it is in contact with blood or when it is placed in situ (deploy) in another most (most) cavity or space in the body.

The materials disclosed herein are often capable of being prepared and stored as a monomer component or as a single vial formulation until needed. They have the ability to reliably and predictably transition from a liquid state to a solid state, which is important for their administration through catheters, cannulas, syringes, and the like.

In certain embodiments, the composition can be administered to an aqueous fluid environment, such as blood, in which the composition forms a single aggregate structure. In other words, it is sufficiently cohesive before, during and after in vivo polymerization to minimize or eliminate fragmentation, disintegration and separation. The exothermic rate of polymerization of the present invention is sufficiently low that heat does not adversely affect surrounding tissues that may be heat sensitive.

In certain embodiments, the tissue toxicity and cytotoxicity of the alkyl cyanoacrylate polymer is sufficiently low such that it is well tolerated in vivo. In certain embodiments, the compositions of the present invention can be used to fill, enclose, partially fill, or partially enclose an unfilled volume or space in a substance (mass).

Administration of drugs

In certain embodiments, the alkyl cyanoacrylate formulations can be utilized in a variety of medical procedures including, but not limited to, treatment of cerebral aneurysms, arteriovenous malformations, treatment of uterine fibroids, treatment of abdominal aortic aneurysms, and endoleaks caused by vascular stenting.

In one embodiment, for example, in the treatment of a cerebral aneurysm, a microcatheter is advanced under fluoroscopy to the location of the aneurysm. If desired, an occlusive balloon is used to inhibit vascular flow during the procedure. A single vial of the medical grade alkyl cyanoacrylate preparation is transferred through a catheter into the aneurysm until the aneurysm is filled. Care is taken to maintain the overall integrity of the implant material so that no particles or debris separate from the implant. Cyanoacrylate polymerizes upon standing due to contact with blood. To create laminar blood flow, the polymerized cyanoacrylate is shaped during and after placement using a balloon or other tool to create a smooth surface for blood flowing through the aneurysm site. This greatly reduces the risk of thrombosis and thus stroke. If the aneurysm is located in a branch of a vessel, cyanoacrylate can be shaped to create a wedge-shaped shunt, the tip of which extends in the opposite direction of blood flow, smoothly directing and shunting the blood flow into each downstream vessel.

In typical embodiments, the alkyl chain length of the alkyl portion of the cyanoacrylate is greater than 4 carbon atoms, more typically 5 to 10 carbon atoms or 5 to 7 carbon atoms, and most typically 6 carbon atoms. N-hexyl cyanoacrylate is particularly preferred due to a combination of desirable morphology, viscosity, and biocompatibility when combined with other components of the formulation. These include cohesive structures such that no fragments separate from the body of the implant material; viscosity, allowing injection through a microcatheter while remaining integral after injection; low toxicity; good in vivo tolerance; and formability during surgery, allowing for shaping for optimal blood flow.

Certain embodiments disclosed herein include medical grade compositions suitable for application to or in the human body, comprising a mixture of:

(a) a polymerizable alkyl cyanoacrylate monomer or oligomer;

(b) at least one polymerization inhibitor;

(c) a contrast agent; and

(d) plasticizer

Wherein the composition is capable of being sealed in a single container and is stable for more than one month at room temperature and is capable of being adapted to polymerize in vivo.

In certain embodiments, the alkyl cyanoacrylate can be an oligomer. For example, the oligomer can be 2-hexyl cyanoacrylate, n-hexyl cyanoacrylate, pentyl cyanoacrylate, heptyl cyanoacrylate, octyl cyanoacrylate, and the like. In exemplary embodiments, the oligomer can be a n-hexyl cyanoacrylate oligomer.

In certain embodiments, the medical grade composition can include a plasticizer. For example, the plasticizer can be butyl benzyl phthalate, dibutyl phthalate, diethyl phthalate, dimethyl phthalate, dioctyl phthalate, trialkyl acylcitrates, benzoic acid esters of dihydroxy and polyhydroxy branched aliphatic compounds, tricresyl phosphate, and the like. In certain embodiments, the plasticizer can be an acyl trialkyl citrate where each alkyl group independently has from 1 to 10 carbon atoms. For example, alkyl acylcitrates include, but are not limited to, trimethyl O-acetyl citrate, triethyl O-acetyl citrate, tri-n-propyl O-acetyl citrate, tri-n-butyl O-acetyl citrate, tri-n-pentyl O-acetyl citrate, tri-n-hexyl O-acetyl citrate, trimethyl O-propionyl citrate, triethyl O-propionyl citrate, tri-n-propyl O-propionyl citrate, tri-n-butyl O-propionyl citrate, tri-n-pentyl O-propionyl citrate, tri-n-hexyl O-propionyl citrate, trimethyl O-butyryl citrate, triethyl O-butyryl citrate, tri-n-propyl O-butyryl citrate, tri-n-butyl O-butyryl citrate, tri-n-pentyl O-butyryl citrate, tri-n-hexyl O-butyryl citrate, and the like. In typical embodiments, the plasticizer can be O-acetyl tri-n-butyl citrate.

In certain embodiments, the medical-grade composition can include a polymerization inhibitor, for example, the polymerization inhibitor can be 4-methoxyphenol, 2, 6-di-tert-butyl-4-methylphenol, hydroquinone, phosphoric acid, sulfur dioxide (SO)₂) Any combination thereof, and the like. In typical embodiments, the polymerization inhibitor can be 2, 6-di-tert-butyl-4-methylphenol, 4-methoxyphenol, sulfur dioxide, and any combination thereof.

In certain embodiments, the medical grade composition can include a contrast agent. For example, the contrast agent can be gold, platinum, tantalum, titanium, tungsten, and barium sulfate, any combination thereof, and the like. In typical embodiments, the contrast agent can be gold.

In certain embodiments, the medical grade composition can include an alkyl cyanoacrylate monomer and an alkyl cyanoacrylate oligomer. In certain embodiments, the alkyl cyanoacrylate oligomer can have a viscosity of from about 5 centipoise to about 1000 centipoise. In typical embodiments, the alkyl cyanoacrylate oligomer can have a viscosity of from about 10 centipoise to about 100 centipoise. In a more typical embodiment, the alkyl cyanoacrylate oligomer can have a viscosity of from about 15 centipoise to about 35 centipoise.

In certain embodiments, the medical grade composition can be substantially free of viscosity altering amounts of alkyl cyanoacrylate polymer.

In certain embodiments, the medical-grade composition can be in a single container that is substantially opaque to ultraviolet and/or visible light. This does not require that the container must be completely light tight; conversely, instead of being completely opaque, a partially opaque vial (e.g., of brown glass) may be used. Alternatively, in certain embodiments, the medical-grade composition can be in a single container that is visible light-transmissive or semi-visible light-transmissive.

Certain embodiments disclosed herein include a method of preparing an alkyl cyanoacrylate monomer of formula (I)

Wherein R is an alkyl group of 4 to 10 carbon atoms, including:

(a) reacting formaldehyde with a compound of formula (1-A) in the presence of a catalyst,

to provide an alkyl cyanoacrylate partial polymer, wherein R is as defined above for formula I;

(b) adding a compound selected from the group consisting of 4-methoxyphenol, 2, 6-di-tert-butyl-4-methylphenol, SO to a portion of the polymer of alkyl cyanoacrylate₂And any combination thereof;

(c) containing a compound selected from 4-methoxyphenol, 2, 6-di-tert-butyl-4-methylphenol, SO₂Cracking a portion of the polymer of the alkyl cyanoacrylate in a vessel of a second polymerization inhibitor, and any combination thereof, to provide a cracked alkyl cyanoacrylate;

(d) containing a compound selected from 4-methoxyphenol, 2, 6-di-tert-butyl-4-methylphenol, SO₂Distilling the cracked alkyl cyanoacrylate in (c) in a vessel of a third polymerization inhibitor, and any combination thereof, to provide an alkyl cyanoacrylate monomer fraction;

(f) the third polymerization inhibitor is removed from the alkyl cyanoacrylate monomer fraction.

In certain embodiments, the purity of the alkyl cyanoacrylate monomer of formula (I) can be 95% to 100%. In typical embodiments, the purity of the alkyl cyanoacrylate monomer of formula (I) can be 98% to 100%. In a more typical embodiment, the purity of the alkyl cyanoacrylate monomer of formula (I) can be from 99% to 100%.

Certain embodiments disclosed herein include a method of preparing a medical grade alkyl cyanoacrylate composition in a single container, comprising:

(a) photochemically treating an alkyl cyanoacrylate monomer to provide an alkyl cyanoacrylate oligomer capable of having a viscosity of from about 5 to about 1000 centipoise;

(b) the alkyl cyanoacrylate oligomer is mixed with a plasticizer solution including a plasticizer and a polymerization inhibitor to provide an alkyl cyanoacrylate oligomer plasticizer mixture.

In certain embodiments, the plasticizer of the plasticizer solution in the medical grade composition can include butyl benzyl phthalate, dibutyl phthalate, dimethyl phthalate, dioctyl phthalate, acyl trialkyl citrates, benzoates of dihydroxy and polyhydroxy branched chain aliphatic compounds, tri-p-cresol phosphate, any combination thereof, and the like. In certain embodiments, the plasticizer can be an acyl trialkyl citrate where each alkyl group independently has from 1 to 10 carbon atoms. For example, the alkyl acylcitrate may include trimethyl O-acetyl citrate, triethyl O-acetyl citrate, tri-n-propyl O-acetyl citrate, tri-n-butyl O-acetyl citrate, tri-n-pentyl O-acetyl citrate, tri-n-hexyl O-acetyl citrate, trimethyl O-propionyl citrate, triethyl O-propionyl citrate, tri-n-propyl O-propionyl citrate, tri-n-butyl O-propionyl citrate, tri-n-pentyl O-propionyl citrate, tri-n-hexyl O-propionyl citrate, trimethyl O-butyryl citrate, triethyl O-butyryl citrate, tri-n-propyl O-butyryl citrate, tri-n-butyl O-butyryl citrate, tri-n-pentyl O-propionyl citrate, tri-n-propionyl citrate, tri-butyl O-propionyl citrate, tri-n-propyl O-, Tri-n-hexyl O-butyryl citrate, any combination thereof and the like. In typical embodiments, the plasticizer can be O-acetyl tri-n-butyl citrate.

In certain embodiments, the inhibitor solution in the medical grade composition can be 4-methoxyphenol, 2, 6-di-tert-butyl-4-methylphenol, hydroquinone, phosphoric acid, sulfur dioxide (SO)₂) Any combination thereof, and the like.

In certain embodiments, the medical grade composition can include combining a contrast agent with an alkyl cyanoacrylate oligomer plasticizer mixture. In certain embodiments, the contrast agent can be gold, platinum, tantalum, titanium, tungsten, and barium sulfate, any combination thereof, and the like. In typical embodiments, the contrast agent can be gold.

In certain embodiments, a single container of medical grade composition can be stored in a single container that is opaque to visible light. Alternatively, in certain embodiments, the medical-grade composition can be stored in a single container that is visible light-transmissive or semi-visible light-transmissive.

Certain embodiments disclosed herein include a method of providing a single container of an alkyl cyanoacrylate formulation, comprising:

(a) alkyl cyanoacrylate monomers of formula (I)

Wherein R is an alkyl group of 4 to 10 carbon atoms,

which is capable of forming alkyl cyanoacrylate oligomers with ultraviolet radiation,

wherein the alkyl cyanoacrylate monomer of formula (I) can have a viscosity of from about 3 centipoise to about 5 centipoise; and is

The alkyl cyanoacrylate oligomer can have a viscosity of about 10 centipoise to about 1000 centipoise

(b) Combining alkyl cyanoacrylate oligomers with a plasticizer and a polymerization inhibitor to provide an alkyl cyanoacrylate oligomer plasticizer mixture

(c) The resulting alkyl cyanoacrylate oligomer plasticizer mixture is placed in a single container such that the resulting single container alkyl cyanoacrylate formulation is stable for more than one month at room temperature and is capable of being polymerized in vivo.

In certain embodiments, the plasticizer of the single container alkyl cyanoacrylate formulation can be an acyltrialkyl citrate. In certain embodiments, the inhibitor for the single container alkyl cyanoacrylate formulation can be 4-methoxyphenol, 2, 6-di-tert-butyl-4-methylphenol, hydroquinone, phosphoric acid, sulfur dioxide (SO)₂) And any combination thereof.

In certain embodiments, a single container of the alkyl cyanoacrylate formulation can include a contrast agent. For example, the contrast agent can be selected from gold, platinum, tantalum, titanium, tungsten, iodine compounds, barium sulfate, and the like.

In certain embodiments, a single container of an alkyl cyanoacrylate formulation can be opaque to light. Alternatively, in certain embodiments, a single container of the alkyl cyanoacrylate formulation can be visible light-transmissive or semi-visible light-transmissive.

Certain embodiments disclosed herein include compositions comprising:

(a) alkyl cyanoacrylate oligomers;

(b) at least one polymerization inhibitor;

(c) a contrast agent; and

(d) plasticizer

Wherein the alkyl cyanoacrylate oligomer can be prepared from an alkyl cyanoacrylate monomer;

the composition is stable for more than one month in a single container, and

the composition is capable of polymerizing to form an aggregated structure when it is contacted with an anionic environment.

In certain embodiments, in a composition comprising an alkyl cyanoacrylate oligomer, at least one polymerization inhibitor, a contrast agent, and a plasticizer, the alkyl cyanoacrylate oligomer can be a n-hexyl cyanoacrylate oligomer. In typical embodiments, the n-hexyl cyanoacrylate oligomer can have a viscosity of 5 to 1000 centipoise. In a more typical embodiment, the n-hexyl cyanoacrylate oligomer can have a viscosity of 15 to 100 centipoise. In a most typical embodiment, the n-hexyl cyanoacrylate oligomer can have a viscosity of 20 to 35 centipoise.

In certain embodiments, in a composition comprising an alkyl cyanoacrylate oligomer, at least one polymerization inhibitor, a contrast agent, and a plasticizer, the polymerization inhibitor can be 4-methoxyphenol, 2, 6-di-tert-butyl-4-methylphenol, sulfur dioxide (SO)₂) Hydroquinone, phosphoric acid, any combination thereof, and the like.

In certain embodiments, in the composition comprising the alkyl cyanoacrylate oligomer, the at least one polymerization inhibitor, the contrast agent, and the plasticizer, the contrast agent can be selected from gold, platinum, tantalum, titanium, tungsten, barium sulfate, and the like. In typical embodiments, the contrast agent can be gold.

In certain embodiments, a single container can be opaque to visible light in a composition comprising an alkyl cyanoacrylate oligomer, at least one polymerization inhibitor, a contrast agent, and a plasticizer. Alternatively, in certain embodiments, a single container can be visible light-transmissive or visible light-semi-transmissive.

In certain embodiments, a single container may include sulfur dioxide in a composition comprising an alkyl cyanoacrylate oligomer, at least one polymerization inhibitor, a contrast agent, and a plasticizer. In typical embodiments, the amount of sulfur dioxide in the composition can be from 5ppm to 500 ppm. In a more typical embodiment, the amount of sulfur dioxide in the composition can be from 10ppm to 100 ppm.

Certain embodiments disclosed herein include a method of making an embolic agent comprising:

(a) mixing an alkyl cyanoacrylate and a plasticizer solution to provide an alkyl cyanoacrylate oligomer plasticizer solution

(b) Mixing the alkyl cyanoacrylate oligomer plasticizer solution and contrast agent in a single container to provide a pre-sterilized mixture

(c) Storing the pre-sterilized mixture under an inert atmosphere

(d) Heating a single container containing the pre-sterilized mixture to a temperature sufficient to sterilize the pre-sterilized mixture

Wherein the alkyl cyanoacrylate oligomer has a viscosity of from about 15 centipoise to about 500 centipoise; and is

The embolic agent can be stable for more than one month.

In certain embodiments, the plasticizer solution in the embolic agent can be selected from the group consisting of acyl trialkyl citrates, one or more polymerization inhibitors, and any combination thereof. In typical embodiments, the plasticizer solution can be selected from the group consisting of tributyl O-acetyl citrate, p-methoxyphenol, 2, 6-di-t-butyl-4-methylphenol, sulfur dioxide, and any combination thereof.

In certain embodiments, the contrast agent of the embolic agent can be gold, platinum, tantalum, titanium, tungsten, barium sulfate, and any combination thereof. In typical embodiments, the contrast agent can be gold.

In typical embodiments, the pre-sterilization mixture can be sterilized. For example, the pre-sterilization mixture can be sterilized by radiation or heat. In typical embodiments, the pre-sterilization mixture can be sterilized by heating. For example, in exemplary embodiments, the temperature sufficient to sterilize the pre-sterilization mixture is from about 150 ℃ to about 200 ℃.

In certain embodiments, a single container containing an embolic agent can be opaque to visible light. Alternatively, in certain embodiments, a single container can be visible light-transmissive or visible light-semi-transmissive.

Certain embodiments disclosed herein include a formulation for remodeling a body space, comprising:

alkyl cyanoacrylate in an amount up to about 50 weight percent;

a plasticizer mixture in an amount up to about 30 weight percent, wherein the plasticizer mixture consists of acyl trialkyl citrate, 4-methoxyphenol, 2, 6-di-tert-butyl-4-methylphenol, sulfur dioxide, and mixtures thereof; and

a contrast agent in an amount up to 50 weight percent, wherein the contrast agent is selected from the group consisting of gold, platinum, tantalum, titanium, tungsten, and barium sulfate; and is

The formulation is chemically and physically stable in a single bottle for at least 30 days at room temperature. In preferred embodiments, the formulation is stable at room temperature for at least about 45 days, preferably 2, 3, 4, 5 or 6 months, most preferably one year, 18 months or two years.

In certain embodiments, the alkyl cyanoacrylate in the formulation used to remodel the body space can be n-hexyl cyanoacrylate. In typical embodiments, the n-hexyl cyanoacrylate can be an n-hexyl cyanoacrylate oligomer.

In certain embodiments, the trialkyl acylcitrate in the formulation for remodeling the body space can be tri-n-butyl O-acetyl citrate.

In certain embodiments, the contrast agent in the formulation for remodeling the body space can be gold.

One embodiment disclosed herein includes a kit for embolizing a body cavity, comprising a formulation for remodeling a body space in a single container and a catheter or syringe configured for introducing an embolization treatment product into the body cavity, wherein the kit comprises written instructions or information.

Certain embodiments can include a process for preparing an alkyl cyanoacrylate monomer of formula (I), wherein R can be an alkyl group of 4 to 10 carbon atoms

In typical embodiments, the alkyl cyanoacrylate monomers of formula (I) can be prepared by reacting formaldehyde with the compound of formula (1-A) in a solvent and in the presence of a secondary amine to form an alkyl cyanoacrylate,

wherein R is as defined above for formula (I). For example, the secondary amine can be piperidine, dimethylamine, and the like. In certain embodiments, the solvent can be subsequently removed by distillation to provide an alkyl cyanoacrylate residue. For example, the alkyl cyanoacrylate residue can be a partial polymer, a polymer, or the like.

In certain embodiments, a solvent can be added to the alkyl cyanoacrylate residue to form an alkyl cyanoacrylate solvent mixture. Typically, the solvent can be one that forms an azeotrope with the residual solvent remaining after removal of the first solvent. For example, the solvent can be a solvent such as toluene, benzene, and the like. In certain embodiments, the solvent can be removed. For example, the solvent can be azeotropically removed by distillation to provide crude alkyl cyanoacrylate, e.g., crude alkyl cyanoacrylate partial polymer, crude alkyl cyanoacrylate polymer, combinations thereof, and the like.

In certain embodiments, polyphosphoric acid and a polymerization inhibitor can be added to the alkyl cyanoacrylate. In typical embodiments, the polymerization inhibitor can be 2, 6-di-tert-butyl-4-methylphenol, 4-methoxyphenol, SO₂Any combination thereof, and the like. Further, in certain embodiments, any residual solvent can be removed under vacuum. For example, the residual solvent can be removed by distillation under reduced pressure.

In certain embodiments, crude alkyl cyanoacrylate can be heated to provide alkyl cyanoacrylate monomer. For example, crude alkyl cyanoacrylate can be depolymerized and gaseous alkyl cyanoacrylate monomer can be collected in a vessel containing a polymerization inhibitor. In typical embodiments, the alkyl cyanoacrylate can be depolymerized by cracking. For example, crude alkyl cyanoacrylate can be heated to about 150 ℃ to about 210 ℃ under a vacuum of about 5mmHg to about 0.1 mmHg. The gaseous alkyl cyanoacrylate monomer can be collected by condensation into a vessel containing a polymerization inhibitor. In one embodiment, the vacuum does not exceed 200 ℃ and the vacuum is from about 5mmHg to about 1 mmHg. In certain embodiments, the vacuum can be broken with an inert gas such as argon or nitrogen, followed by SO₂A cover system.

In certain embodiments, the alkyl cyanoacrylate monomer can be further purified by distillation. Such as distillation under reduced pressure. In a typical embodiment, the alkyl cyanoacrylate monomer can be distilled under vacuum and collected into a vessel containing a polymerization inhibitor. For example, the polymerization inhibitor can be 2, 6-di-tert-butyl-4-methylphenol, 4-methoxyphenol, SO₂Any combination thereof, and the like. In exemplary embodiments, the vacuum can be from 5mmHg to about 0.1 mmHg. In a most typical embodiment, the vacuum can be 5mmHg to about 1mmHg and the polymerization inhibitor can be 4-methoxyphenol, 2, 6-di-tert-butyl-4-methylPhenol, SO₂Any combination thereof, and the like. Further, in certain embodiments, the vacuum can be broken with an inert gas such as argon, nitrogen, and the like. In certain embodiments, the system can be subsequently coated with SO₂To provide a pure alkyl cyanoacrylate monomer inhibitor mixture.

In certain embodiments, the polymerization inhibitor can be removed by a polymerization inhibitor remover and the SO can be removed by bubbling an inert gas through the pure alkyl cyanoacrylate monomer solution₂To provide a pure alkyl cyanoacrylate monomer free of polymerization inhibitor.

Examples

The following examples are given to enable those skilled in the art to more clearly understand and practice the present invention. The examples should not be construed as limiting the scope of the invention but as illustrating and representing the invention.

Example 1

Preparation of stabilized n-hexyl cyanoacrylate

Step (a) preliminary reaction

Formaldehyde particles (290g, 9.7 moles) were charged to a 3000mL three-necked reactor equipped with a Dean-Stark distillation apparatus, followed by 650mL of methanol and finally 4.8mL of piperidine. The reaction mixture was stirred using an overhead stirrer and heating was started. The mixture was heated to 65 ℃ to 80 ℃ and held in this range for 45 minutes, during which time the solution became "milky". The temperature was reduced to-55 ℃ and n-hexyl cyanoacrylate (1600g, 8.8 mol) was added slowly. During the addition of n-hexyl cyanoacrylate, the temperature was maintained at 68 ℃ to 75 ℃. The color of the reaction mixture turned slightly yellow upon completion of the addition. The residual n-hexyl cyanoacrylate was washed into the reaction mixture through the addition funnel with an additional 100ml of methanol.

The reaction was heated to reflux and about 610ml of methanol was removed by Dean-Stark distillation over-1 hour (during which the reaction temperature rose from 72 ℃ to 78 ℃), at which time n-hexyl cyanoacrylate formed. Subsequently, 630ml of toluene were added via an addition funnel. The mixture containing n-hexyl cyanoacrylate was heated and the residual methanol and piperidine were removed by azeotropic distillation occurring at 84 ℃ to 115 ℃ (uncorrected temperature). The distillation was stopped when the temperature rose to 115 ℃. The system was allowed to cool to room temperature.

Step (b) cracking process

The reaction apparatus was reassembled and the Dean-Stark distillation apparatus was replaced with a grignard (Vigreux) distillation column. A condenser fitted with a receiving flask was connected to the distillation column. The system is set up so that a vacuum can be applied if necessary. To the reaction vessel were added 50mg of polyphosphoric acid and 0.8g of 4-methoxyphenol, and then the system was sealed.

The receiving flask was cooled using liquid nitrogen, then the mixture was stirred and the system was placed under vacuum (5mmHg to 1mm Hg). The degree of vacuum was adjusted by introducing argon gas. The reaction vessel was kept below 150 ℃ and the liquid fraction containing all toluene added was collected by distillation. The vacuum was broken with argon and the system was covered with SO₂For 3 seconds. The receiving flask containing toluene was replaced with a pre-weighed receiving flask containing 4-methoxyphenol (10mg per 100mL container capacity, e.g., a 1L container containing 100mg of 4-methoxyphenol). The apparatus is placed under vacuum (5mmHg to 1mmHg) and then the reaction vessel is heated to about 170 ℃ to about 190 ℃ (no more than 200 ℃) to initiate cracking of the polymer, with n-hexyl cyanoacrylate monomer distilled off at 80 ℃ to 95 ℃ under the vacuum described above. 50mL to 100mL of the n-hexyl cyanoacrylate forecut was collected and discarded, the vacuum broken with argon and the system covered with SO₂For 3 seconds. The receiving flask containing the forecut was replaced with a pre-weighed receiving flask containing 4-methoxyphenol (10mg per 100mL container capacity, e.g., a 1L container containing 100mg of 4-methoxyphenol). The apparatus is placed under vacuum (5mmHg to 1mmHg) and then the reaction vessel is heated to about 170 ℃ to about 190 ℃ (no more than 200 ℃) to initiate cracking of the polymer, with monomer distilling off at 80 ℃ to 95 ℃ under the vacuum described above. When the light yellow n-hexyl cyanoacrylate monomer can not be collected any more, stopHeating, breaking the vacuum with argon and then coating the system with SO₂For 3 seconds. Including the step of exchanging the receiving vessel, the monomer is collected at a rate of about 1 liter per day. Care was taken in the foregoing process to maintain a non-reactive atmosphere covering the reaction mixture and the resulting product, thereby avoiding unwanted polymerization and degradation reactions. This in turn improves the quality and purity of the final product, making it stable in a single vial formulation.

Step (c) distillation process

A vacuum distillation apparatus was set up with a 2L flask (three-necked round bottom flask), a magnetic stirrer and a Grignard distillation column. The distillation apparatus was placed under argon and the light yellow n-hexyl cyanoacrylate distilled from the cracking step was added to the distillation flask. The holding device was under argon and covered with SO₂For 3 seconds, and stirring of the liquid in the distillation flask was started. The receiving flask was cooled with liquid nitrogen, and then the distillation apparatus was placed under vacuum (5mmHg to 1 mmHg). The pale yellow n-hexyl cyanoacrylate was gradually heated with stirring until distillation started. Fractions were collected at a rate of one drop per minute. After collection of-50 ml of the front fraction, the vacuum was broken with argon and then covered with SO₂. The forecut was discarded and a second receiving flask containing 4-methoxyphenol (10mg/100mL container capacity) was placed to receive the cut. Several fractions were collected and the last 100mL fraction could be discarded. Each time the flask was changed, the vacuum was broken with argon and the system was then covered with SO₂. Collecting the mixture containing 4-methoxyphenol and SO₂The pure n-hexyl cyanoacrylate of (1) was used in the next step.

Example 2

Photochemical adjustment of cyanoacrylate monomer viscosity

Aldrich HQ from Sigma-Aldrich of St.Louis, Mo.S.A.&MEHQ inhibitor remover (catalog #306320 2006 2005-) -purified n-hexyl cyanoacrylate containing 4-methoxyphenol from example 1 was treated to remove p-methoxyphenol, and then n-hexyl cyanoacrylate monomer was bubbled through argon to remove SO₂. Free of 4-methoxyphenol and SO₂The purified n-hexyl cyanoacrylate of (1) has a viscosity of 4 centipoise.

Purified n-hexyl cyanoacrylate (500g) was then introduced into an Ace Glass photochemical reactor equipped with a medium pressure quartz mercury vapor lamp. N-hexyl cyanoacrylate is irradiated until the liquid has a viscosity of from about 20 to about 35 centipoise. The resulting oligomeric material is referred to as component a. This viscosity adjustment allows the final product to have a viscosity high enough to allow the injected composition to remain as an intact substance where it is placed, but also low enough to allow it to be injected through a microcatheter and thus be suitable for use in the vasculature of a patient.

Example 3

Preparation of the plasticizer component

A stock solution of O-acetyl tri-n-butyl citrate containing 4-methoxyphenol and 2, 6-di-tert-butyl-4-methylphenol was prepared as follows. To O-acetyl tri-n-butyl citrate (500g, 1.24 moles) was added 4-methoxyphenol (750PPM) and 2, 6-di-tert-butyl-4-methylphenol (750PPM) under argon. The mixture was stirred to homogeneity. Bubbling sulfur dioxide (SO) through a solution of tri-n-butyl O-acetylcitrate containing 4-methoxyphenol and 2, 6-di-tert-butyl-4-methylphenol₂600 PPM). The resulting material is referred to as component B.

Example 4

And (3) component C: formulations of component A and component B

UV-treated n-butyl cyanoacrylate (component A, 500g) was combined with component B (250g) at room temperature and mixed to a homogeneous phase. The resulting product has a viscosity of about 20 to about 35 centipoise. The above combination of component a and component B gives component C.

Example 5

Preparation of Single bottle formulation

Component C (1.5mL) was added to a 5mL vial containing fine mesh gold (0.9g), and the vial was placed under argon. The vial is then sealed and heat sterilized. The single vial formulation is stable over one year.

Example 6

Preparation of 2-hexyl cyanoacrylate

This contemplated process is based on the process for preparing n-hexyl cyanoacrylate taught in the previous examples.

A5-liter three-necked flask in a 5-liter heating mantle was equipped with a reflux condenser, a Dean-Stark separator (trap), an addition funnel, and a mechanical stirrer with a glass stirring paddle. The following components were added to the flask: paraformaldehyde granules (136g, 4.5 moles), methanol (300mL), and pyridine (2.2 mL). The reaction mixture was stirred and heated to 65 ℃ to 80 ℃ for 45 minutes. The heat was cooled to-55 ℃ and 2-hexyl cyanoacrylate (736g, 4.1 moles) was then added dropwise through the addition funnel. The reaction was exothermic and the rate of addition was adjusted to maintain the reaction mixture temperature at 68 ℃ to 75 ℃. The addition funnel was rinsed with an additional 46mL of methanol. The distilled methanol was collected from the reaction flask by a Dean-Stark trap. The recovery amount was measured. Distillation was continued over an hour until more than 80% of the original volume of methanol was recovered. Toluene (290mL) was then added via an addition funnel. The mixture was heated to remove residual methanol and piperidine by azeotropic distillation, which occurred at 84 ℃ to 115 ℃ (uncorrected temperature). The distillation was stopped when the temperature reached 115 ℃. The system was allowed to cool to room temperature before the reaction apparatus was reconstituted for the next step.

The recombination reaction device replaces the Dean-Stark distillation device with a Grignard distillation column, and a condenser and a receiving flask are connected to the Grignard distillation column. The system is set up so that a vacuum can be applied if necessary. Polyphosphoric acid (23mg) and 4-methoxyphenol (0.37g) were added to the reaction vessel, and the system was sealed.

The receiving flask was cooled with liquid nitrogen and thenThe mixture was stirred and the system was placed under vacuum (5mmHg to 1 mmHg). The degree of vacuum was adjusted by introducing argon gas. The reaction vessel was maintained below 150 ℃ and the liquid fraction containing the remaining toluene was collected. The applied vacuum was separated from the system phase and broken with argon. Then, the system was covered with SO₂For 3 seconds.

The vacuum was broken with argon and the system was then placed in SO₂The mixture was left for 3 seconds. The collection vessel containing the fractions is replaced with a pre-weighed collection vessel containing 4-methoxyphenol (10mg per 100mL of vessel volume, e.g., a 1L vessel containing 100mg of 4-methoxyphenol). The reaction apparatus was placed under vacuum (0.1-0.5mmHg) and the reaction vessel was heated to about 170 ℃ to about 190 ℃ (no more than 200 ℃) to begin cracking the polymer. Collecting and discarding 50mL to 100mL 2-hexyl cyanoacrylate precut, breaking the vacuum with argon and coating the system with SO₂For 3 seconds. The collection flask containing the forecut was replaced with a pre-weighed collection vessel containing 4-methoxyphenol (10mg per 100mL container capacity, e.g., a 1L container containing 100mg of 4-methoxyphenol). The apparatus is placed under vacuum (5mmHg to 1mmHg), then the reaction vessel is heated to about 170 ℃ to about 190 ℃ (no more than 200 ℃) to begin cracking the polymer, and the monomer fraction is distilled off at 80 ℃ to 95 ℃ under the vacuum described above. The collection vessel containing 2-hexyl cyanoacrylate monomer was replaced with another empty, pre-weighed collection vessel containing 4-methoxyphenol (10mg/100mL vessel volume) and the procedure repeated until the majority of 2-hexyl cyanoacrylate monomer was collected (each time the flask was exchanged with sulfur dioxide). Including the step of exchanging the receiving vessel, the monomer was collected at a rate of 1L per day.

Example 7

Preparation of n-pentyl cyanoacrylate

This contemplated process is based on the process for preparing n-hexyl cyanoacrylate taught in the previous examples.

A10 liter three-necked flask was equipped with a reflux condenser, Dean-Stark separator, addition funnel, and mechanical stirrer. The following components were added to the flask: paraformaldehyde granules (272g, 9 moles), methanol (600mL), and pyridine (4.4 mL). The reaction mixture was stirred and heated to 65 ℃ to 80 ℃ for 45 minutes. The heat was removed and the mixture was cooled to-55 ℃ before n-pentyl cyanoacrylate (1372g, 8.2 moles) was added dropwise through the addition funnel. The reaction was exothermic and the rate of addition was adjusted to maintain the temperature of the reaction mixture between 68 ℃ and 75 ℃. The addition funnel was rinsed with an additional 92mL of methanol. Methanol was distilled and collected from the reaction flask through a Dean-Stark trap. Distillation was continued over an hour period until more than 80% of the original volume of methanol was recovered. Toluene (580mL) was then added via an addition funnel. The mixture was heated to remove residual methanol and piperidine by azeotropic distillation, which occurred at 84 ℃ to 115 ℃ (uncorrected temperature). The distillation was stopped when the temperature reached 115 ℃. The system was allowed to cool to room temperature before the reaction apparatus was reconstituted for the next step.

The recombination reaction device replaces the Dean-Stark distillation device with a Grignard distillation column, and a condenser and a receiving flask are connected to the Grignard distillation column. The system is set up so that a vacuum can be applied if necessary. Polyphosphoric acid (46mg) and 4-methoxyphenol (0.74g) were added to the reaction vessel, and the system was sealed.

The receiving flask was cooled with liquid nitrogen, then the mixture was stirred and the system was placed under vacuum (5mmHg to 1 mmHg). The degree of vacuum was adjusted by introducing argon gas. The reaction vessel was maintained below 150 ℃ and the liquid fraction containing the remaining toluene was collected. The applied vacuum was separated from the system phase and broken with argon. Then, the system was covered with SO₂For 3 seconds.

The vacuum was broken with argon and the system was then placed in SO₂The mixture was left for 3 seconds. The collection vessel containing the fractions is replaced with a pre-weighed collection vessel containing 4-methoxyphenol (10mg per 100mL of vessel capacity, e.g., a 1L vessel containing 100mg of 4-methoxyphenol). The reaction apparatus was placed under vacuum (0.1-0.5mmHg) and the reaction vessel was heated to about 170 deg.C to about 190 deg.C (not more than 200 deg.C) toCracking of the polymer begins. Collecting and discarding 50mL to 100mL n-pentyl cyanoacrylate precut, breaking the vacuum with argon and covering the system with SO₂For 3 seconds. The collection flask containing the forecut was replaced with a pre-weighed collection vessel containing 4-methoxyphenol (10mg per 100mL container capacity, e.g., a 1L container containing 100mg of 4-methoxyphenol). The apparatus is placed under vacuum (5mmHg to 1mmHg), then the reaction vessel is heated to about 170 ℃ to about 190 ℃ (no more than 200 ℃) to begin cracking the polymer, and the monomer fraction is distilled off at 80 ℃ to 95 ℃ under the vacuum described above. The collection vessel containing n-pentyl cyanoacrylate monomer was replaced with another empty, pre-weighed collection vessel containing 4-methoxyphenol (10mg/100mL of vessel volume) and the procedure repeated until the majority of n-pentyl cyanoacrylate monomer was collected (with each exchange of the flask with sulfur dioxide). Including the step of exchanging the receiving vessel, the monomer was collected at a rate of 1L per day.

Claims (42)

1. A medical grade composition suitable for application to or in the human body comprising a mixture of:

(a) a polymerizable alkyl cyanoacrylate monomer or oligomer;

(b) at least one polymerization inhibitor;

(c) a contrast agent; and

(d) plasticizer

Wherein the composition is sealed in a single container, stable for more than one month at room temperature, and suitable for polymerization in vivo.

2. The composition of claim 1 wherein the alkyl cyanoacrylate is an oligomer and is selected from the group consisting of 2-hexyl cyanoacrylate, n-hexyl cyanoacrylate, pentyl cyanoacrylate, heptyl cyanoacrylate, and octyl cyanoacrylate.

3. The composition of claim 1, wherein the alkyl cyanoacrylate is an oligomer of n-hexyl cyanoacrylate.

4. The composition of claim 1 wherein the polymerization inhibitor is selected from the group consisting of 4-methoxyphenol, 2, 6-di-tert-butyl-4-methylphenol, hydroquinone, phosphoric acid, sulfur dioxide (SO)₂) And any combination thereof.

5. The composition of claim 4, wherein the polymerization inhibitor is 4-methoxyphenol, 2, 6-di-tert-butyl-4-methylphenol, and sulfur dioxide.

6. The composition of claim 1, wherein the plasticizer is O-acetyl tri-n-butyl citrate.

7. The composition of claim 1, wherein the contrast agent is selected from the group consisting of gold, platinum, tantalum, titanium, tungsten, and barium sulfate, and any combination thereof.

8. The composition of claim 7, wherein the contrast agent is gold.

9. The composition of claim 1 comprising an alkyl cyanoacrylate monomer and an alkyl cyanoacrylate oligomer.

10. The composition of claim 1 having a viscosity of from about 15 to about 35 centipoise.

11. The composition of claim 1 which is substantially free of viscosity altering amounts of alkyl cyanoacrylate polymer.

12. The composition of claim 1, wherein the single container is substantially opaque to ultraviolet light.

13. Process for preparing alkyl cyanoacrylate monomers of formula (I)

Wherein R is an alkyl group of 4 to 10 carbon atoms, comprising:

(a) reacting formaldehyde with a compound of formula (1-A) in the presence of a catalyst,

to provide a partial polymer of alkyl cyanoacrylate;

(b) adding a compound selected from the group consisting of 4-methoxyphenol, 2, 6-di-tert-butyl-4-methylphenol, SO to a portion of the polymer of alkyl cyanoacrylate₂A first polymerization inhibitor, and any mixtures thereof;

(c) with a compound selected from 4-methoxyphenol, 2, 6-di-tert-butyl-4-methylphenol, SO₂And any mixtures thereof, cracking a portion of the polymer of the alkyl cyanoacrylate to provide a cracked alkyl cyanoacrylate;

(d) with a compound selected from 4-methoxyphenol, 2, 6-di-tert-butyl-4-methylphenol, SO₂And any mixtures thereof, distilling the cracked alkyl cyanoacrylate in (c) to provide an alkyl cyanoacrylate monomer fraction; and

(e) removing the third polymerization inhibitor from the alkyl cyanoacrylate monomer fraction.

14. The process of claim 13, wherein the purity of the alkyl cyanoacrylate monomer of formula (I) is 98% to 100%.

15. A process for preparing a medical grade alkyl cyanoacrylate composition in a single container comprising:

(a) photochemically treating an alkyl cyanoacrylate monomer to provide an alkyl cyanoacrylate oligomer having a viscosity of from about 5 to about 1000 centipoise; and

(b) the alkyl cyanoacrylate oligomer is combined with a plasticizer and a polymerization inhibitor to provide an alkyl cyanoacrylate oligomer plasticizer mixture.

16. The method of claim 15, wherein

The plasticizer is an acyl trialkyl citrate; and is

The polymerization inhibitor is selected from 4-methoxyphenol, 2, 6-di-tert-butyl-4-methylphenol, hydroquinone, phosphoric acid and sulfur dioxide (SO)₂) And any combination thereof.

17. The method of claim 15, further comprising:

combining a contrast agent with the alkyl cyanoacrylate oligomer plasticizer mixture,

wherein the contrast agent is selected from the group consisting of gold, platinum, tantalum, titanium, tungsten, and barium sulfate, and any combination thereof.

18. The composition of claim 15, wherein the single container is substantially opaque to ultraviolet light.

19. A method of providing a single container formulation of an alkyl cyanoacrylate comprising:

(a) providing an alkyl cyanoacrylate oligomer of the monomer of formula (I),

wherein R is an alkyl group of 4 to 10 carbon atoms and the monomer has a viscosity of about 3 centipoise to about 5 centipoise prior to oligomerization; and

the alkyl cyanoacrylate oligomer has a viscosity of about 10 to 1000 centipoise;

(b) combining the alkyl cyanoacrylate oligomer with a plasticizer and a polymerization inhibitor to provide an alkyl cyanoacrylate oligomer plasticizer mixture; and

(c) the resulting alkyl cyanoacrylate oligomer plasticizer mixture is placed in a single container, and the resulting single container alkyl cyanoacrylate formulation is stable for more than one month at room temperature and is suitable for polymerization in vivo.

20. The method of claim 19, wherein the plasticizer is a trialkyl acylcitrate; and the polymerization inhibitor is selected from 4-methoxyphenol, 2, 6-di-tert-butyl-4-methylphenol, hydroquinone, phosphoric acid and sulfur dioxide (SO)₂) And any combination thereof.

21. The method of claim 19, further comprising:

combining the alkyl cyanoacrylate oligomer with a contrast agent, wherein the contrast agent is selected from the group consisting of gold, platinum, tantalum, titanium, tungsten, iodine compounds, and barium sulfate.

22. The method of claim 18, wherein the single container is opaque to ultraviolet light.

23. A composition comprising:

(a) alkyl cyanoacrylate oligomers;

(b) at least one polymerization inhibitor;

(c) a contrast agent; and

(d) a plasticizer;

wherein the alkyl cyanoacrylate oligomer is prepared from the alkyl cyanoacrylate monomer of claim 13;

wherein the composition is stable for more than one month in a single container, and

when the composition is exposed to an anionic environment it polymerizes to form a polymeric structure.

24. The composition of claim 23, wherein the alkyl cyanoacrylate oligomer is a n-hexyl cyanoacrylate oligomer.

25. The composition of claim 24, wherein the n-hexyl cyanoacrylate has a viscosity of from 15 to 500 centipoise.

26. The composition of claim 23 wherein the polymerization inhibitor is selected from the group consisting of 4-methoxyphenol, 2, 6-di-tert-butyl-4-methylphenol, sulfur dioxide (SO)₂) Hydroquinone, phosphoric acid, and any combination thereof.

27. The composition of claim 23, wherein said contrast agent is selected from the group consisting of gold, platinum, tantalum, titanium, tungsten, and barium sulfate.

28. The composition of claim 27, wherein the contrast agent is gold.

29. The composition of claim 23, wherein the single container is substantially opaque to ultraviolet light.

30. A composition, comprising:

(a) an alkyl cyanoacrylate oligomer, wherein from about 30% to about 50% by weight of the composition is the alkyl cyanoacrylate oligomer, wherein the alkyl cyanoacrylate oligomer has a viscosity of from about 15 centipoise to about 500 centipoise;

(b) a plasticizer mixture, wherein 10% to 30% by weight of the composition is the plasticizer mixture; and

(c) a contrast agent, wherein 30% to 50% by weight of the composition is the contrast agent,

wherein the composition is stable stored therein for at least about one month in a single container and at room temperature.

31. The composition of claim 30 wherein the plasticizer mixture consists of tributyl 2-acetyl citrate, 4-methoxyphenol, and 2, 6-di-tert-butyl-4-methylphenol;

wherein the amount of 4-methoxyphenol is from about 100 to about 500ppm, and

wherein the amount of 2, 6-di-tert-butyl-4-methylphenol is about 100 to about 500 ppm.

32. The composition of claim 30, further comprising sulfur dioxide.

33. The composition of claim 30, wherein the single container is opaque to visible light.

34. A method of making an embolic agent comprising:

(a) combining an alkyl cyanoacrylate oligomer with a plasticizer solution and a contrast agent to form a mixture;

(b) sealing the mixture in a single container under an inert atmosphere; and

(c) heating a container containing the mixture to a temperature sufficient to sterilize the mixture; wherein the alkyl cyanoacrylate oligomer has a viscosity of from about 15 centipoise to about 500 centipoise; and the sterilized mixture is stable for storage at room temperature for at least about 1 month.

35. The method of claim 34, wherein the plasticizer solution is selected from the group consisting of tributyl 2-acetyl citrate, p-methoxyphenol, 2, 6-di-t-butyl-4-methylphenol, sulfur dioxide, and any combination thereof.

36. The method of claim 34, wherein said contrast agent is selected from the group consisting of gold, platinum, tantalum, titanium, tungsten, and barium sulfate.

37. The composition of claim 36, wherein the contrast agent is gold.

38. The method of claim 34, wherein the temperature sufficient to sterilize the mixture is from about 150 ℃ to about 200 ℃.

39. The method of claim 34, wherein the single container is substantially opaque to ultraviolet light.

40. A formulation for remodeling a body space, comprising:

alkyl cyanoacrylate in an amount up to about 50 weight percent;

a plasticizer mixture in an amount up to about 30 weight percent, wherein the plasticizer mixture consists of trialkyl acylcitrates, 4-methoxyphenol, 2, 6-di-tert-butyl-4-methylphenol, sulfur dioxide, and mixtures thereof; and

a contrast agent in an amount up to about 50 weight percent, wherein the contrast agent is selected from the group consisting of gold, platinum, tantalum, titanium, tungsten, and barium sulfate; wherein the formulation is chemically and physically stable for at least 30 days at room temperature in a single sealed container.

41. The formulation of claim 40, wherein the alkyl cyanoacrylate is n-hexyl cyanoacrylate; the acyl trialkyl citrate is O-acetyl tri-n-butyl citrate; and the contrast agent is gold.

42. A kit for embolizing a body cavity, comprising the formulation of claim 40 and a catheter or syringe configured to introduce the formulation into a body cavity.