JP2011513337A - Methods and compositions for treating disc herniation - Google Patents

Abstract

Treating herniated discs by locally administering one or more biodegradable drug depots containing a therapeutically effective amount of glucocorticoid to or near the herniated disc to reduce the size of the herniated disc Methods and compositions for doing so are provided.
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Description

  This application includes US Provisional Application No. 61/046218, filed Apr. 18, 2008, entitled “Fluocinolone Formulations in A Biodegradable Polymer Carrier” and “Biodegradable Materials”. Claiming filing date benefit based on US patent application Ser. No. 12 / 105,864, filed Apr. 18, 2008, entitled “Dexamethasone Formulations in Biodegra Material”. All of these disclosures are hereby incorporated by reference into the present disclosure.

  Intervertebral hernia is a troublesome disorder of the spinal column, causing significant pain and muscle dysfunction in patients and can be debilitating. Pain from disc herniation can last for as long as 6 months or, if severe, for years.

  The spinal column consists of a series of bones called connected vertebrae that surround the spinal cord and protect it from injury. Nerves diverge from the spinal cord and spread to other parts of the body, enabling communication between the brain and the body. The vertebrae of the spine are connected by a spongy intervertebral disc and two small joints called the facet joints. The intervertebral disc and intervertebral joint are located between the vertebrae and together allow vertebral movement.

  The intervertebral disc constitutes a strong connective tissue that holds one vertebra to the next, and acts as a cushion or shock absorber between the vertebrae. The intervertebral disc consists of a strong outer layer called the annulus fibrosus and a gel-like center called the nucleus pulposus. The annulus is a strong radial tire-like structure composed of lamellae, ie, concentric sheets of collagen fibers connected to the vertebral endplate. The annulus is confining the gel-like nucleus pulposus.

  Disc herniation may be caused by sudden back injury or gradual wear and tear of the disc (also called disc degeneration). As a person ages, the center of the disc begins to lose moisture and the effectiveness of the disc as a cushion becomes less. As the intervertebral disc deteriorates, the annulus fibrosus may tear. This may allow the nucleus pulposus to travel through the rift in the annulus and into the space occupied by the nerves and spinal cord. The herniated disc can then compress the nerve (also called nerve pinch) and cause pain, sensory paralysis, stinging, or limb weakness.

  Intervertebral hernia can occur in any disc in the spinal column, but hernias in the lumbar and cervical vertebrae are most common. Intervertebral disc herniation in the cervical vertebrae can cause pain relief and upper limb muscular dysfunction, commonly referred to as cervical rhizopathy. On the other hand, herniated discs in the lumbar vertebrae can induce pain relief and lower limb muscle dysfunction commonly referred to as sciatica.

  Treatment of herniated discs includes anti-inflammatory drug therapies such as steroids and non-steroidal anti-inflammatory drugs (NSAIDs), physical therapy, behavior modification, intravertebral electrothermal therapy (IDET), and surgery. The surgery can be performed percutaneously as either an open surgery or a mini-open procedure using a very small open incision, or using specially designed instruments and radiographic techniques.

  Surgical treatment of a herniated disc to remove the hernia portion of the disc annulus and relieve pressure on the spinal nerve compromises the integrity of the annulus. This can lead to re-herniation or more likely leakage of the nucleus pulposus from the disc nucleus through the weakened zone of the annulus and onto the nerve complex surrounding the disc and adjacent to the disc. Often results in an annulus fibrosis. The nucleus pulposus produces a highly inflammatory response around the exposed nerve complex, causing persistent disc-induced pain. This phenomenon, sometimes referred to as inductive leaky disc syndrome, is a common side effect associated with procedures that remove the hernia portion of the disc annulus.

  There remains a need for new compositions and methods for treating disc herniation and the pain and / or inflammation associated with this debilitating condition. New compositions and methods that reduce the size of the herniated disc by increasing nucleus pulposus resorption are most beneficial.

  Novel compositions and methods are provided for effectively reducing, preventing, or treating disc herniation. In various embodiments, glucocorticoid compositions and methods are provided that reduce hernia size with a single drug depot or multiple drug depots. Novel glucocorticoid compositions and methods are provided that can easily allow accurate and precise implantation of drug depots containing glucocorticoids with minimal physical and psychological trauma to the patient. One advantage of a glucocorticoid drug depot composition and method is that the drug depot can now be easily delivered to a target tissue site (eg, near the nucleus pulposus or spinal column) and the drug depot. It is possible to reduce, prevent or treat intervertebral hernia with an agent. Thus, accurate and precise implantation of the drug depot can be accomplished with minimally invasive procedures to treat disc herniation.

  In one embodiment, there is provided a method of treating disc herniation in a patient in need of such treatment, wherein the method comprises one or more biodegradable drug depots comprising a therapeutically effective amount of glucocorticoids. Or in the vicinity thereof, wherein the one or more biodegradable drug depots are capable of releasing an effective amount of glucocorticoid for at least 3 days to 6 months. In some embodiments, the glucocorticoid can be released from the drug depot for about 6 weeks to about 3 months.

  In another embodiment, an implantable drug depot useful for treating an intervertebral disc herniation in a patient in need of such treatment is provided, wherein the implantable drug depot comprises a therapeutically effective amount of a glucocorticoid. Wherein the depot is implantable at or near disc herniation, wherein the drug depot is supplemented with about 0.5% to about 40% by weight of glucocorticoid and an effective amount of glucocorticoid. It is capable of releasing corticoids for at least 3 days to 8 weeks.

  In yet another embodiment, a method for reducing the size of an intervertebral hernia in a patient is provided, the method administering one or more biodegradable drug depots comprising fluocinolone to or near the intervertebral hernia. Wherein the one or more biodegradable drug depots are capable of releasing fluocinolone for at least 3 days to 2 months and reducing the size of the disc herniation by at least 50%.

  Additional features and advantages of the various embodiments will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the various embodiments. The objectives and other advantages of the various embodiments will be realized and attained by means of the elements and combinations particularly pointed out in the description and appended claims.

  Other aspects, features, benefits and advantages of the embodiments will become apparent to some extent by attention to the following description, appended claims and accompanying drawings.

FIG. 1A is a cross-sectional view of a target tissue site that is an unruptured disc herniation. FIG. 1B is a cross-sectional view of a target tissue site that is a disc herniation that has ruptured. FIG. 2 is a cross-sectional view illustrating one embodiment of an implantable drug depot having an anchor tied to the drug depot with a thread (eg, suture, twist, etc.), the drug depot having a ring It is administered in the intervertebral disc. FIG. 3 shows three treatment groups (one group using a drug depot containing fluocinolone in poly (lactide-co-glycolide) (PLGA) placed 1.5 cm from the nucleus pulposus; one group Were transplanted into and removed from multiple rats, divided into 0 cm from the nucleus pulposus, using a drug depot containing fluocinolone in PLGA; group 3 used control pellets) FIG. 5 is a bar graph illustrating weight percent of nucleus pulposus. Fluocinolone increased the absorption of the nucleus pulposus, especially when placed immediately next to the nucleus pulposus. FIG. 4 is a graphical representation of the cumulative release% of fluocinolone depot over 60 days in vitro, and a graphical representation of the amount of fluocinolone (μg) released daily from the drug depot.

  It should be understood that the figures are not drawn as measured on a scale. Furthermore, the relationships between objects in the figure may not be measured on a scale and may actually have an inverse relationship with respect to size. The figures are intended to provide an understanding and clarity regarding the structure of each object shown, and therefore some features may be exaggerated to illustrate certain features of the structure. .

  For purposes of this specification and the appended claims, unless stated otherwise, used in the amounts of ingredients, percentages or ratios of materials, all numbers expressing reaction conditions, and in the specification and claims. Other numerical values should be understood to be modified by the term “about” in all cases. Accordingly, unless specified otherwise, the numerical parameters set forth in the following specification and appended claims are approximations that can be varied depending upon the desired properties sought to be obtained by the present invention. At a minimum, and not as an attempt to limit the application of the doctrine of equivalents to the claims, each numeric parameter considers at least the reported significant number of digits and applies normal rounding techniques Should be interpreted.

  Although the numerical ranges and parameters representing the broad scope of the present invention are approximate, the numerical values shown in the specific examples are reported as accurately as possible. All numerical values, however, inherently contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements. Moreover, all ranges disclosed herein are to be understood to encompass any and all subranges subsumed therein. For example, a range of “1-10” is any and all subranges between a minimum value of 1 and a maximum value of 10 (and inclusive), ie, a minimum value equal to or greater than 1 And any and all subranges having a maximum value equal to or less than 10, eg, 5.5-10.

  As used in this specification and the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless clearly and undoubtedly limited to one reference. Includes things. Thus, for example, reference to “a drug depot” includes one, two, three or more drug depots.

  Reference will now be made in detail to some embodiments of the invention, examples of which are illustrated in the accompanying drawings. While the invention will be described in conjunction with the illustrated embodiments, it is to be understood that these embodiments are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of the present invention as defined by the appended claims.

The headings below are not meant to limit the present disclosure in any way, and one optional subtitle embodiment can be used in conjunction with another optional subtitle embodiment.
Novel compositions and methods are provided for effectively reducing, preventing, or treating disc herniation. In various embodiments, glucocorticoid compositions and methods for reducing hernia size with a single drug depot or multiple drug depots are provided. Novel glucocorticoid compositions and methods are provided that can easily allow accurate and precise implantation of drug depots containing glucocorticoids with minimal physical and psychological trauma to the patient. One advantage of glucocorticoid drug depot compositions and methods is that the drug depot can now be easily delivered to a target tissue site (eg, near the nucleus pulposus or spinal column) and the drug depot is The ability to reduce, prevent or treat herniated discs. Thus, accurate and precise drug depot implantation can be accomplished with minimal invasive procedures to treat disc herniation.

  In one embodiment, a method of treating disc herniation in a patient in need of such treatment is provided, the method comprising administering one or more biodegradable drug depots containing a therapeutically effective amount of glucocorticoid to the disc. Administration at or near the hernia, wherein the one or more biodegradable drug depots are capable of releasing an effective amount of a glucocorticoid for at least 3 days to 6 months.

In another embodiment, reducing herniated disc using one or more drug depots that release an effective amount of fluocinolone or dexamethasone, or a pharmaceutically acceptable salt thereof, for at least 1 week to 6 weeks, Methods for preventing or preventing are provided.
Glucocorticoids Glucocorticoids are included in drug depots. The drug depot includes a physical structure to facilitate sustained release of the drug in the desired site (eg, the patient's disc space, spinal canal, disc herniation, etc.). Drug depots also include drugs. The term “drug” as used herein is generally meant to refer to any substance that alters the physiology of a patient. The term “drug” can be used interchangeably herein with the terms “therapeutic agent”, “therapeutically effective amount”, and “active pharmaceutical ingredient” or “API”. It should be understood that a “drug” formulation can include more than one therapeutic agent, where a typical combination of therapeutic agents includes a combination of two or more drugs. The drug depot comprises a concentration gradient of the therapeutic agent around the depot for delivery to the site. In various embodiments, the drug depot provides an optimal drug concentration gradient of the therapeutic agent at a distance from about 0.1 cm to about 5 cm from the implantation site.

  A “therapeutically effective amount”, or “effective amount” is such that when administered, the drug results in a change in biological activity such as, for example, preventing inflammation, reducing or alleviating pain, reducing or ameliorating a condition. It is an amount. In various embodiments, a therapeutically effective amount of glucocorticoid is an amount that prevents, reduces or treats herniated disc.

  In some embodiments, administration of the glucocorticoid can be administered locally at a low dose not exceeding 100 μg / kg / day. In some embodiments, the dosage range may be from about 100 μg / kg / day to about 1 pg / kg / day. In some embodiments, the glucocorticoid can be administered at a dosage of about 50 μg / kg / day to about 100 pg / kg / day, or about 30 μg / kg / day to about 500 pg / kg / day. The dose administered to a patient depends on the pharmacokinetic properties of the drug being administered, the route of administration, the patient's condition and characteristics (sex, age, weight, health status, physique), severity of symptoms, combination treatment, treatment frequency It should be understood that a single depot or multiple depots can be present depending on various factors including the desired effect.

  Glucocorticoids are a class of steroids characterized by their ability to bind to glucocorticoid receptors. Glucocorticoids have broadband anti-inflammatory and immunosuppressive effects. They act by inhibiting leukocyte migration; interfering with leukocyte, fibroblast, and endothelial cell function; and suppressing the synthesis and action of inflammatory cytokines, including interleukin-6. Glucocorticoids affect glucose metabolism. As used herein, glucocorticoids have at least some glucocorticoid activity and can optionally have some mineral corticoid activity.

  As used herein, “glucocorticoid” includes glucocorticoids or pharmaceutically acceptable salts thereof; pharmacologically active derivatives of glucocorticoids or active metabolites of glucocorticoids. As used herein, a pharmaceutically acceptable salt refers to a derivative of a disclosed compound (eg, an ester or an amine), where the parent compound prepares its acidic or basic salt. Can be modified. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts include the normal non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such normal non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, or nitric acid; or acetic acid, furic acid, propionic acid, succinic acid Acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamonic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, Salts prepared from organic acids such as fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid are included. Pharmaceutically acceptable also individually include racemic mixtures of glucocorticoids ((+)-R and (-)-S enantiomers) or dextrorotatory and levorotatory isomers, respectively. Glucocorticoids may be in the free acid or base form or may be PEGylated for long acting activity. In some embodiments, the glucocorticoid is in the form of a stearate ester.

  Suitable glucocorticoids include, but are not limited to, alcomethasone, aldosterone amsinonide, 21-acetoxypregnenolone, algeston, amsinonide, beclomethasone, betamethasone, budesonide, beclomethasone, budesonide, ciclesonide, clobetasol, clobetaprezone, crocortotron, crocortotron, crocortron Nord, cortibazole, chloroprednisone, corticosterone, cortisone, deflazacort, deoxycorticosterone, dezonide, desoxycorton, desoxymethazone, dexamethasone, dexamethasone acetate, dexamethasone phosphate disodium salt, diflorazone, diflucortron, diflu Predonate, Enoxolone, Fluazacoat, Flumethasone, Flunisolide, Fluocinolone, Fu Ocinolone acetonide or stearate, fluperolone acetate, fluprednide acetate, fluprednisolone, flulandrenolide, fluticasone propionate, flurchlorone, fludrocortisone, fludroxycortide, flumethasone, flunisolide, fluocinonide, fluocortin, fluocortron, fluoro Metron, fluperolone, flupredidene, fluticasone, formomocoltal, halcinonide, halometasone, halobetasol propionate, halopredone acetate, hydrocortamate, hydrocortisone, hydrocortisone aceponate, hydrocortisone buteplate, hydrocortisone butyrate, loteprednol etabonate, roteprednol etabonate Magipredon, Medrizone, Meprednisone, Mometasone Flow , Medrizone, Meprednisone, Methylprednisolone, Methylprednisolone Aceponate, Mometasone furoate, Parameterzone, Prednicarbate, Prednisone, Prednisolone, Prednylidene, Parameterzone, Prednisolone, Prednisolone 25-diethylamino-acetate, Prednisolone phosphate Sodium, prednisone, prednival, prednylidene, rimisolone, thixortorol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexaacetonide, urobetasol, or a pharmaceutically acceptable salt or ester or amine thereof, and combinations thereof Is included.

  Glucocorticoids are distinguished from mineralcorticoids and sex steroids by their specific receptors, target cells, and effects. For example, mineralocorticoids, on the other hand, exert their effects in the kidney, causing selective excretion of excess potassium in the urine and at the same time storing and / or storing sodium. On the other hand, sex steroids such as the female hormones estrogen and progesterone and the male hormone testosterone are used for male / female development.

In an exemplary embodiment for preventing, reducing or treating disc herniation, the glucocorticoid comprises fluocinolone or a pharmaceutically acceptable salt thereof. Some examples of potential pharmaceutically acceptable salts include salt-forming salts with acids and bases that do not substantially increase the toxicity of the compound, such as alkali metals and ammonium such as magnesium, potassium, etc. Salts of inorganic acids such as hydrochloric acid, hydroiodic acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid and sulfuric acid, and tartaric acid, acetic acid, citric acid, malic acid, benzoic acid, glycolic acid, gluconic acid , Salts of organic acids such as sulphonic acid, succinic acid, aryl sulfonic acid (eg p-toluene sulfonic acid). To the extent that fluocinolone salts can be created for safe administration to mammals, those salts are included within the scope of this application. Further, when referring to fluorocinolone, the active ingredient may be in basic form (eg, free acid), amine, ester, or racemic form, or combinations thereof, as well as in salt form.
Fluorocinolone Fluocinolone is available from several pharmaceutical manufacturers. In various embodiments, the fluocinolone comprises fluocinolone acetonide. The dosage of fluocinolone may be approximately 0.0005 to approximately 100 μg / kg / day. Further doses of fluocinolone include about 0.0005 to about 95 μg / kg / day, about 0.0005 to about 90 μg / kg / day, about 0.0005 to about 85 μg / kg / day, about 0.0005 to about 80 μg / kg / day, approximately 0.0005 to approximately 75 μg / kg / day, approximately 0.001 to approximately 70 μg / kg / day, approximately 0.001 to approximately 65 μg / kg / day, approximately 0.001 to approximately 60 μg / day kg / day, approximately 0.001 to approximately 55 μg / kg / day, approximately 0.001 to approximately 50 μg / kg / day, approximately 0.001 to approximately 45 μg / kg / day, approximately 0.001 to approximately 40 μg / kg / day Days, approximately 0.001 to approximately 35 μg / kg / day, approximately 0.0025 to approximately 30 μg / kg / day, approximately 0 0025 to approximately 25 μg / kg / day, approximately 0.0025 to approximately 20 μg / kg / day, and approximately 0.0025 to approximately 15 μg / kg / day. In another embodiment, the dosage of fluocinolone is from approximately 0.005 to approximately 15 μg / kg / day. In another embodiment, the dosage of fluocinolone is from approximately 0.005 to approximately 10 μg / kg / day. In another embodiment, the dosage of fluocinolone is from approximately 0.005 to approximately 5 μg / kg / day. In another embodiment, the dosage of fluocinolone is approximately 0.005-2.5 μg / kg / day. In some embodiments, the amount of fluocinolone is 0.001-600 μg / day. In some embodiments, the amount of fluocinolone is from 0.0025 to 400 μg / day. In some embodiments, the amount of fluocinolone added in one or more drug depots may be between 0.5 wt% and 20 wt%.

  In some embodiments, fluocinolone is removed from the depot from about 10 pg to about 10 mg / hour, from about 100 pg to about 1 mg / hour, from about 1 ng to about 100 μg / hour, from about 10 ng to about 10 μg / hour, from about 100 ng to about 1 μg. Per hour, or at a dose of about 500 μg / hour. In various embodiments, the dosage may be a pulse dose of about 10 pg to about 10 mg / day, or about 100 pg to about 0.02 μg / day.

FIG. 4 is a graphical representation of the in vitro% cumulative release profile for a drug depot containing 1% fluocinolone. The drug depot elutes at 0.0025 to about 0.0125 μg / day over 60 days and releases at least 40% of the fluocinolone added in the drug depot over 60 days. A fluocinolone depot suitable for use in the present application is a provisional US patent application filed April 18, 2008 entitled "Fluocinolone Formulations in A Biodegradable Polymer Carrier". No. 61/046218.
Dexamethasone In one exemplary embodiment for preventing, reducing or treating disc herniation, the glucocorticoid comprises dexamethasone. When referring to dexamethasone, unless otherwise specified or apparent from the context, we are to be construed to also refer to a pharmaceutically acceptable salt. Some examples of potentially pharmaceutically acceptable salts include salt-forming acid and base salts that do not substantially increase the toxicity of the compound, for example, alkali metal and ammonium salts such as magnesium, potassium, Salts of inorganic acids such as hydrochloric acid, hydroiodic acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid and sulfuric acid, as well as tartaric acid, acetic acid, citric acid, malic acid, benzoic acid, glycolic acid, gluconic acid, gulonic acid And salts of organic acids such as succinic acid and arylsulfonic acid (eg, p-toluenesulfonic acid). To the extent that dexamethasone salts can be created for safe administration to mammals, those salts are included within the scope of this application. When referring to dexamethasone, the specification also includes dexamethasone acetate and / or dexamethasone sodium phosphate unless otherwise specified.

  Furthermore, when referring to dexamethasone, the active ingredient may be in basic form (eg, free acid) as well as in salt form. In various embodiments, if the active ingredient is in acid form, the presence of severe polymer degradation such that the active ingredient may be observed with thermal or solvent processing that may be performed using PLGA or PLA. It can be combined with the polymer under conditions that do not. In various embodiments, the drug depot contains about 5 wt% to about 20 wt% dexamethasone acetate and the polymer contains 75/25 or 85/25 PLGA, POE, or SAIB, with or without mPEG. contains.

  Dexamethasone is available from several manufacturers. In various embodiments, dexamethasone is administered from the depot from about 10 pg to about 10 mg / hour, from about 100 pg to about 1 mg / hour, from about 1 ng to about 100 μg / hour, from about 10 ng to about 10 μg / hour, from about 100 ng to about 1 μg / hour. It can be released at a dose of 500 μg / hour. In various embodiments, the dosage may be about 0.01 to about 10 mg / kg / day, or about 1 mg to about 120 mg / day. A dexamethasone depot suitable for use in this application is US patent application Ser. No. 12 / 105,864, filed Apr. 18, 2008, entitled “Dexamethasone Formulations in A Biodegradable Material”. It is described in.

In addition to the glucocorticoid, the drug depot can contain one or more additional therapeutic agents. Examples of therapeutic agents include agents that are direct- and local-acting modulators of pro-inflammatory cytokines such as TNF-α and IL-1, such as, but not limited to, soluble tumor necrosis factor α receptor, any PEGylated soluble tumor necrosis factor alpha receptor, monoclonal or polyclonal antibodies or antibody fragments, or combinations thereof. Examples of suitable therapeutic agents include receptor antagonists (molecules that compete with the receptor for binding to the target molecule), antisense polynucleotides, and transcription inhibitors of DNA encoding the target protein. Suitable examples include, but are not limited to, adalimumab, infliximab, etanercept, pegsnercept (PEGsTNF-R1), sTNF-R1, CDP-870, CDP-571, CNI-1493, RDP58, ISIS 104838, 1 → 3. -Β-D-glucan, Renercept, PEG-sTNFRIIFc muteins, D2E7, aferimomab, and combinations thereof. In other embodiments, the therapeutic agent includes a metalloprotease inhibitor, glutamate antagonist, glial cell-derived neurotrophic factor (GDNF), B2 receptor antagonist, substance P receptor (NK1) antagonist such as capsaicin and cibamid. Inhibitors of downstream regulatory element antagonistic modulators (DREAM), iNOS, tetrodotoxin (TTX) resistant Na ⁺ channel receptor subtypes PN3 and SNS2, interleukins (IL-1, IL-6 and IL-8, and anti Recombinant adeno-associated virus (rAAV) vectors encoding inhibitors such as inflammatory cytokines), TNF binding proteins, onercept (r-hTBP-1), inhibitors, activators, enhancers or neutralizers, But not limited to naturally occurring or synthetic Double-stranded, single-chain containing antibiotics or fragments thereof are included. For example, a suitable therapeutic agent is based on a single chain antibody, called Nanobodies ™ (Ablynx, Ghent, Belgium) and defined as the smallest functional fragment of a naturally occurring single domain antibody Includes molecules. Alternatively, therapeutic agents include agents that inhibit mitogen-activated protein kinase (MAPK), p38MAPK, Src, or protein tyrosine kinase (PTK) that affect kinases and / or transmit cellular signals. . Therapeutic agents include, for example, Gleevec, Herceptin, Iressa, Imatinib (STI571), Herbimycin A, Tyrphostin 47, Elvstatin, Genistein, Staurosporine, PD98059, SB203580, CNI-1493, VX-50 / 702 (Vertex) / Kissei), SB203580, BIRB796 (Boehringer Ingelheim), Glaxo P38 MAP kinase inhibitor, RWJ67657 (J & J), UO126, Gd, SCIO-469 (Scios), RO3201195 (Roche), semi-mod PharmaSciences), or derivatives thereof.

  The therapeutic agent, in various embodiments, blocks transcription or translation of TNF-α or other proteins in the inflammatory cascade. Suitable therapeutic agents include, but are not limited to, integrin antagonists, α-4-β-7-integrin antagonists, cell adhesion inhibitors, interferon γ antagonists, CTLA4-Ig agonists / antagonists (BMS) -188667), CD-40 ligand antagonist, humanized anti-IL-6 mAb (MRA, tocilizumab, Chugai), HMGB-1 mAb (Critical Therapeutics), anti-IL2R antibody (daclizumab, basiliximab), ABX (anti-IL-8 antibody) ), Recombinant human IL-10, or HuMax IL-15 (anti-IL15 antibody).

  Other suitable therapeutic agents include IL-1 inhibitors such as Kineret® (Anakinra), a recombinant non-glycosylated form of human interleukin-1 receptor antagonist (IL-1Ra), or IL AMG108, a monoclonal antibody that blocks the action of -1. Therapeutic agents also include glutamate antagonists or inhibitors that bind to excitatory amino acids such as glutamate and aspartate, NMDA receptors, AMPA receptors, and / or kainate receptors. For example, interleukin-1 receptor antagonist, thalidomide (TNF-α release inhibitor), thalidomide analog (reducing TNF-α production by macrophages), bone morphogenetic protein (BMP) type 2 and BMP-4 (caspase) 8 inhibitors, TNF-α activator), quinapril (upregulates TNF-α, angiotensin II inhibitor), interferons such as IL-11 (modulates TNF-α receptor expression), and aurintricarboxylic acid (Inhibits TNF-α) may also be useful as therapeutic agents to reduce inflammation. It is contemplated that PEGylated forms of the drug can be used if desired. Examples of other therapeutic agents include NFκB inhibitors such as clonidine; antioxidants such as dithiocarbamate, and other compounds such as bupivacaine or sulfasalazine.

  Specific examples of therapeutic agents suitable for use include, but are not limited to, anti-inflammatory agents, analgesics, or osteoinductive growth factors, or combinations thereof. Anti-inflammatory drugs include, but are not limited to, salicylate, difunisal, sulfasalazine, indomethacin, ibuprofen, ketorolac, naproxen, tolmethine, diclofenac, ketoprofen, phenamate (mefenamic acid, meclofenamic acid), enolic acid (piroxicam, meloxicam), Celecoxib, etodolac, nimesulide, apazone, sulindac, or tepoxaline; antioxidants such as dithiocarbamate, or other compounds such as sulfasalazine [2-hydroxy-5- [4- [C2-pyridinylamino] sulfonyl] azo] benzoic acid " Or a combination thereof.

  Suitable anabolic or anti-catabolic growth factors include, but are not limited to, bone morphogenetic proteins, growth differentiation factors, LIM mineralization proteins, CDMP or progenitor cells, or combinations thereof.

  Suitable analgesics include, but are not limited to, acetaminophen, lidocaine, bupivacaine, opioid analgesics such as buprenorphine, butorphanol, dextromoramide, dezocine, dextropropoxyphene, diamorphine, fentanyl, al Fentanyl, sufentanil, hydrocodone, hydromorphone, ketobemidone, levometazil, mepyridine, methadone, morphine, nalbuphine, opium, oxycodone, papaveretam, pentazocine, pethidine, phenoperidine, pyritramide, dextropropoxyphene, remifentanyl, thyridine, tramadol, codeine, dicodene, codeine , Meptazinol, dezocine, eptazosin, flupirtine, or combinations thereof.

Analgesics also include agents with analgesic properties such as amitriptyline, carbamazepine, gabapentin, pregabalin, clonidine, or combinations thereof.
The depot can include a muscle relaxant. Typical muscle relaxants include, but are not limited to, arcuronium chloride, atracurium besylate, baclofen, carbolonium, carisoprodol, chlorphenesine carbamate, cyclobenzaprine. , Dantrolene, decamethonium bromide, fazazinium, galamin triethiodide, hexafluorenium, meradrazine, mephenesin, metaxalone, metcarbamol, methocrine iodide, pancuronium, pyridinol mesylate, styramate, skisamethonium, schicetonium, thiocorticoside, thisazine, tolperisone , Tubocurarine, vecuronium, or combinations thereof.

  A depot contains a therapeutic agent or group of therapeutic agents and may also contain other inactive ingredients or excipients. Depots have a multi-purpose purpose including carrying, stabilizing, and controlling the release of therapeutic agent (s). The controlled release method may be, for example, by a solution diffusion mechanism or can be managed by an erosion control method. Typically, a depot is a solid or semi-solid formulation composed of a biocompatible material that may be biodegradable. The term “solid” is taken to mean a stiff material, while “semi-solid” has some flexibility, thereby allowing the depot to meet the requirements of the tissue that bends and surrounds. Interpreted to mean material. Some examples of excipients include, for example, mPEG (methoxypolyethylene glycol), sorbitol, D-sorbitol, maltodextrin, cyclodextrin, β-cyclodextrin, or combinations thereof. Excipients can be added in a weight ratio of 0.5% to 50%.

  In various embodiments, the depot material is durable within the tissue site for a period equal to the planned drug delivery period (for biodegradable ingredients) or beyond (for non-biodegradable ingredients). For example, the depot material can have a melting or glass transition temperature that is near or above body temperature, but below the alteration or decomposition temperature of the therapeutic agent. However, certain erosion of the depot material can also be utilized to provide a sustained release of the added therapeutic agent (s).

  In various embodiments, the drug depot can be designed to release a glucocorticoid when a certain trigger point (eg, temperature, pH, etc.) is reached after implantation in vivo. For example, drug depots contain polymers that release more drug, particularly when the body temperature exceeds 39 ° C. (102 ° F.), for example, if the drug has antipyretic properties like glucocorticoids. be able to. In various embodiments, depending on the site of implantation, the drug depot can release the drug more or less when a particular pH is reached. For example, a drug depot can be designed to release a drug as a body fluid having a specific pH contacts the drug depot (CSF (CSF) is about 7.35 to about 7.70. having a pH, the blood having a pH of about 7.35 to about 7.45, and so on).

  In various embodiments, the depot is such that the glucocorticoid and / or other therapeutic agent comprises about 20-99 wt% of the depot, or 20-95 wt%, or 50-95 wt% of the depot. Can have high drug loading. In various embodiments, the amount of glucocorticoid and / or other therapeutic agent is about 0.1% to about 40% (0.1%, 0.2%, 0%) of the depot in the depot. 5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16 %, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, and any point-to-point range such as 0.1-10%, 10-20%, and 20 -30% etc.). In various embodiments, glucocorticoids can be added in the range of 0.5-20% in the drug depot.

  In an exemplary embodiment, the amount of fluocinolone added can be 1% to 20%, and 100DL, 85/15 PLGA or DL-PLA or DL-PLA, 50/50 PLGA mixture can be added in an amount of about 10-99%. .

  In some embodiments, containing fluocinolone and a polymer, wherein the polymer is poly (lactide-co-glycolide) (PLGA), polylactide (PLA), polyglycolide (PGA), D-lactide, D, L-lactide, There are drug depots comprising L-lactide, D, L-lactide-ε-caprolactone, D, L-lactide-glycolide-ε-caprolactone, or combinations thereof.

  In an exemplary embodiment, the amount of dexamethasone base or acetate is 5% to 20% and 85/15 PLGA or 75/25 PLGA, or POE, or SAIB is added in an amount of about 10% to 98%. be able to. As one skilled in the art will appreciate, when using an implantable elastic depot composition comprising a blend of polymers with different end groups, the resulting formulation has a smaller burst index and controlled delivery duration. For example, polymers with acid (eg, carboxylic acid) and ester end groups (eg, lauryl, methyl, or ethyl ester end groups) can be used.

  In various embodiments, the drug depot is about 0. 1 to 6 months total, 1 to 8 weeks, or 2 to 6 weeks, in order to reduce, prevent or treat disc herniation. 005 to approximately 10 μg / kg / day of glucocorticoid can be released.

  In various embodiments, the drug depot is administered for 3 days to 6 months, or 1 week to 6 weeks after administering the drug depot to or near an intervertebral hernia to reduce, prevent or treat herniated disc. Release 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% of the glucocorticoid. The drug depot is the percentage of active ingredient released in a unit time for a week or 10 days, for example, μg / hour, mg / hour, μg / day, mg / day, 10% / day. It can have a “release rate profile” that refers to days and the like. Those skilled in the art recognize that the release rate profile may be linear, but need not be linear, and may be continuous pulsed administration.

  In some embodiments, the drug depot may not be biodegradable. For example, drug depots include polyurethane, polyurea, polyether (amide), PEBA, thermoplastic elastomeric olefins, copolyesters, and styrenic thermoplastic elastomers, steel, aluminum, stainless steel, titanium, high non-ferrous metal content It can contain metal alloys, carbon fibers, glass fibers, plastics, ceramics, or a combination thereof having an amount and low relative iron ratio. Typically, these classes of drug depots may need to be removed after some time.

  In some cases, it may be desirable to avoid the need to remove the drug depot after use. In those instances, the depot can include a biodegradable material. There are many materials that have the property that they can be used for this purpose and can degrade or disintegrate over a long period of time when placed in or near the target tissue. As a chemical function of the biodegradable material, the mechanism of the degradation process can be essentially hydrolyzable and / or enzymatic. In various embodiments, degradation can occur at the surface (heterogeneous or surface erosion) or can occur uniformly throughout the depot that is the drug delivery system (uniform or bulk erosion).

  Depots include, but are not limited to, capsules, microspheres, microparticles, microcapsules, microfiber particles, nanospheres, nanoparticles, coatings, matrices, wafers, pills, pellets, emulsions, liposomes, micelles, gels, Or other pharmaceutical delivery compositions are included. The drug depot can comprise a pump that holds and administers the medication. In some embodiments, the drug depot has pores that allow release of the drug from the depot. The drug depot allows body fluids to expel the drug in the depot. However, cell entry into the depot is prevented by the pore size of the depot. Thus, in some embodiments, the depot should not function as a tissue scaffold and should not allow tissue growth. Rather, drug depots are utilized only for drug delivery. In some embodiments, the pores in the drug depot are from less than 250 microns to 500 microns. This pore size prevents cells from entering the drug depot and building scaffold cells. Thus, in this embodiment, as the body fluid enters the drug depot, the drug elutes from the drug depot, but the cells are blocked from entering. In some embodiments where there are no or few pores, the drug elutes from the drug depot by enzymatic action, by hydrolysis and / or by other similar mechanisms in the human body.

  Suitable materials for depots are ideally pharmaceutically acceptable biodegradable and / or bioabsorbable materials, preferably GDA approved, or GRAS materials. These materials can be polymeric or non-polymeric, and synthetic or naturally occurring materials, or combinations thereof.

  The term “biodegradable” encompasses the degradation of all or part of a drug depot over time, by enzymatic action, by hydrolytic action, and / or by other similar mechanisms in the human body. In various embodiments, “biodegradable” means that a depot (eg, microparticles, microspheres, gel, etc.) disintegrates into non-toxic components in the body after or while the therapeutic agent is released. Or it can be decomposed. “Bioerodible” means that a depot and / or gel is at least partially eroded or degraded over time, by substances found in surrounding tissues, body fluids, or by cellular action. Means contact. “Bioabsorbable” means that the depot is broken down in the human body and is absorbed, for example, by cells or tissues. “Biocompatible” means that the depot does not cause substantial tissue irritation or necrosis at the target tissue site.

  In various embodiments, the depot can comprise a bioabsorbable, bioerodible and / or biodegradable biopolymer that can provide immediate, sustained or controlled release of the drug. Examples of suitable sustained release biopolymers include, but are not limited to, poly (α-hydroxy acid), poly (lactide-co-glycolide) (PLGA), polylactide (PLA), polyglycolide (PG), Polyethylene glycol (PEG), PEG200, PEG300, PEG400, PEG500, PEG550, PEG600, PEG700, PEG800, PEG900, PEG1000, PEG1450, PEG3350, PEG4500, PEG8000, poly (α-hydroxy acid) complex, polyorthoester, poly Aspirin, polyphosphagen, collagen, starch, pregelatinized starch, hyaluronic acid, chitosan, gelatin, alginate, albumin, fibrin, vitamin E analog (α-tocopheryl acetate, koha Acid d-α-tocopheryl, etc.), D, L-lactide or L-lactide, -caprolactone, D, L-lactide-ε-caprolactone, D, L-lactide-glucolide-ε-caprolactone, dextran, vinylpyrrolidone, polyvinyl Alcohol (PVA), PVA-g-PLGA, PEGT-PBT copolymer (Polyactive), Methacrylate, Poly (N-isopropylacrylamide), PEO-PPO-PEO (Pluronics), PEO-PPO-PAA copolymer, PLGA-PEO-PLGA , PEG-PLG, PLA-PLGA, Poloxamer 407, PEG-PLGA-PEG triblock copolymer, SAIB (sucrose acetate isobutyrate) hydroxypropyl cellulose, hydroxypropyl methyl cell Loose, hydroxyethyl methylcellulose, carboxymethylcellulose or salts thereof, carbopol, poly (hydroxyethyl methacrylate), poly (methoxyethyl methacrylate), poly (methoxyethoxyethyl methacrylate), polymethyl methacrylate (PMMA), methacrylic acid Methyl (MMA), gelatin, polyvinyl alcohol, propylene glycol, or combinations thereof are included.

  In various embodiments, when the drug depot contains a polymer, the polymer is about 0.5 wt% to about 99 wt%, or about 10 wt% to about 99 wt%, or about, based on the weight of the drug depot. 30 wt% to about 60 wt% can be employed.

  Depots include buffers and pH adjusters such as potassium bicarbonate, potassium carbonate, potassium hydroxide, sodium acetate, sodium borate, sodium bicarbonate, sodium carbonate, sodium hydroxide, or sodium phosphate; degradation / release modification Agents; drug release regulators; emulsifiers; preservatives such as benzalkonium chloride, chlorobutanol, phenylmercuric acetate and phenylmercuric nitrate, sodium bisulfite, sodium bisulfate, sodium thiosulfate, thimerosal, methylparaben, polyvinyl alcohol and phenethyl alcohol An inert material such as a solubility modifier; a stabilizer; and / or an agglomeration regulator may optionally be included. Typically, any such inert material is present in the range 0-75 wt%, more typically in the range 0-30 wt%. If the depot is to be placed in the spinal region or joint region, in various embodiments, the depot can contain sterile material without preservatives.

  Depots can exist in various sizes, shapes and forms. There are several factors that can be considered in determining the size, shape and form of a drug depot. For example, both size and shape may allow easy placement of a drug depot at a target tissue site that is selected as an implantation or injection site. In addition, the shape and size of the system should be selected to minimize or prevent migration of the drug depot after implantation or injection. In various embodiments, the drug depot is shaped as a sphere, cylinder (such as a rod or pellet), fiber, flat surface (disk, film, or sheet), and the like. Flexibility can be considered to facilitate placement of the drug depot. In various embodiments, the drug depot can be of various sizes, for example, the drug depot can be about 0.5 mm to 5 mm long and have a diameter of about 0.01 to about 2 mm. . In various embodiments, the drug depot can have a layer thickness of about 0.005-1.0 mm, such as 0.05-0.75 mm.

  X-ray contrast markers can be included on the drug depot to allow the user to place the depot accurately in the target site of the patient. These x-ray contrast markers also allow the user to track the movement and degradation of the depot at the site over time. In this embodiment, the user can use any of a number of diagnostic imaging methods to accurately place the depot in the site. Such diagnostic imaging methods include, for example, X-ray imaging or fluoroscopy. Such x-ray contrast markers include, but are not limited to, barium, calcium, and / or metal beads or particles. When present, x-ray contrast markers are typically about 10% to 40% (10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19 %, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, and 40%, and any range between these two values, such as 10-15%, 15-20%, 20-25%, 25-30%, 30- 35%, 35% -40%, etc., 15-30% being more typical, and even more typically 20-25%). In various embodiments, the x-ray contrast marker may be spherical or a ring around the depot.

  In an exemplary embodiment, a drug depot is provided for delivering a therapeutic agent to a target tissue site under the patient's skin, the drug depot comprising an effective amount of a glucocorticoid, wherein the target tissue The site includes at least one intervertebral disc, spinal foramenity space near the spinal nerve root, intervertebral or synovial joint, or spinal canal.

  In an exemplary embodiment, an implantable drug depot useful for reducing, preventing or treating intervertebral hernia in a patient in need of such treatment is provided, the implantable drug depot comprising: Containing a therapeutically effective amount of fluocinolone or dexamethasone, or a pharmaceutically acceptable salt thereof, the depot can be implanted at a site under the skin to reduce, prevent or treat herniated disc, The drug depot comprises (i) about 0.5 wt% to about 40 wt% fluocinolone or dexamethasone or a pharmaceutically acceptable salt thereof, (ii) about 60 wt% to about 99 wt% polymer, and Optionally (iii) containing 1% to 50% excipient, the drug depot comprising an effective amount of fluocinolone or dexamethasone or the like Pharmaceutically acceptable salts of the ability to release over a period of at least 3 days to 6 months or 1 week to 8 weeks, or 1 week to 6 weeks. In various embodiments, the polymer comprises PLGA, DL-PLA, or a combination thereof, and the excipient comprises mPEG, D-sorbitol, maltodextrin, PEG, cyclodextrin, or a combination thereof.

  In various embodiments, the drug depot contains a gel comprising a material having gelatinous, jelly-like, or colloidal properties at room temperature. The gel, in various embodiments, can have a glucocorticoid dispersed throughout or suspended within the gel and optionally one or more additional therapeutic agents. The therapeutic agent can be dispersed throughout the gel. Alternatively, the concentration of the therapeutic agent can vary throughout. As the biodegradable material of the gel or drug depot degrades at that site, the therapeutic agent (eg, glucocorticoid) is released.

  Where the drug depot is a gel, a higher viscosity gel may be desirable for other applications, as opposed to sprayable gels that typically employ low viscosity polymers, e.g. A gel with a putty-like consistency may be more preferred for disc herniation.

  In another exemplary embodiment, the gel is in a viscous form and is added with one or more drug depots (eg, microspheres loaded with a therapeutic agent), where the viscous gel is , Placed in the synovial joint, intervertebral disc space, spinal canal, or soft tissue surrounding the subject's spinal canal. The gel can also be used in various embodiments to seal or repair tissue and to reduce, prevent or treat disc herniation. In yet another embodiment, the gel is an adhesive gel that is injectable and / or that solidifies upon adhering to the tissue. For example, the gel can be administered as a liquid that gels in place at the target tissue site. In various embodiments, the gel can include a two component system in which a liquid is administered followed by the addition of a gelling agent to gel or cure the liquid.

In various embodiments, the gel is a curable gel, the gel hardens after the gel is applied to the target site, and the drug can be released as body fluid contacts the gel.
In various embodiments, the drug depot is added with glucocorticoid and optionally one or more additional therapeutic agents and delivered to the desired target tissue site (eg, degenerative disc, spinal canal, epidural space, etc.). Is done. In various embodiments, the drug depot can be held in place by sutures, barbs, staples, adhesive gels, etc., which is removed from the site by venous systemic circulation. Or otherwise too widely dispersed to prevent the desired therapeutic effect from being reduced. For example, after several hours or days, the drug depot can degrade, thereby allowing the drug depot (eg, microspheres) to begin releasing the therapeutic agent. Microspheres may not initiate drug release until they are released from the drug depot. Therefore, the microspheres are formed from insoluble or inactive substances that can form soluble or active substances once they come into contact with the labeled tissue site. Similarly, drug depots can contain substances that dissolve or disperse within the tissue. As drug depots begin to dissolve within hours to days, drug depots (eg, microspheres) begin to be exposed to body fluids and release their contents. The drug depot can be formulated to optimize the exposure time of the drug depot and the release of the therapeutic agent from the drug depot.

  In various embodiments, the drug depot (eg, gel) is fluid and can be injected, sprayed, instilled, and / or dispersed on or in the target tissue site. “Flowability” means that the gel formulation is easy to manipulate and can be brushed, sprayed, instilled, injected, molded and / or cast so that it aggregates at or near the target tissue site. Means you can. “Flowability” includes preparations having a low viscosity or a consistency like water to preparations having a high viscosity such as paste-like materials. In various embodiments, the flowability of the formulation allows the formulation to conform to irregularities, tears, cracks, and / or voids in the tissue site. For example, in various embodiments, the gel can be used to fill one or more voids in the spinal column.

  In various embodiments, the drug depot is a poly (α-hydroxy acid), poly (lactide-co-glycolide) (PLGA), polylactide (PLA), polyglycolide (PG), poly (α-hydroxy acid) polyethylene. Glycol (PEG) complex, polyorthoester, polyaspirin, polyphosphagen, collagen, starch, pregelatinized starch, hyaluronic acid, chitosan, gelatin, alginate, albumin, fibrin, vitamin E analog (α-tocopheryl acetate, succinic acid) d-α-tocopheryl, etc.), D, L-lactide or L-lactide, -caprolactone, dextran, vinyl pyrrolidone, poly (vinyl alcohol) (PVA), PVA-g-PLGA, PEGT-PBT copolymer (Polyactive), metacrine Poly (N-isopropylacrylamide), PEO-PPO-PEO (Pluronics), PEO-PPO-PAA copolymer, PLGA-PEO-PLGA, PEG-PLG (poly (d, l-lactide-co-glycolide), PLA -PLGA, poloxamer 407, PEG-PLGA-PEG triblock copolymer, SAIB (sucrose acetate isobutyrate), or combinations thereof, wherein one or more of these components is controlled by a drug depot For example, a drug depot containing a therapeutic agent and a polymer matrix can be injected into the target tissue site, and the polymer matrix can be released over time. (Eg, hours, days) within target tissue site Disintegrates and releases glucocorticoids and optionally additional therapeutic agents, so administration of the drug depot can be localized and performed over a period of time (eg, from at least 1 day to about 1-8 weeks, or More than that).

  The term “sustained release” (eg, extended release or controlled release) as used herein is introduced into the body of a human or other mammal and allows the flow of one or more therapeutic agents over a period of time, and Used to refer to one or more therapeutic agent (s) that are continuously released at a therapeutic level sufficient to achieve a desired therapeutic effect from the beginning to the end of a given period. Reference to a continuous release stream occurs as a result of in vivo biodegradation of the drug depot or matrix or these components, or the metabolic conversion or dissolution of the therapeutic agent (s) or complex of therapeutic agent (s) It is intended to encompass the resulting release.

  In various embodiments, the drug depot can be designed to cause an initial burst administration of the therapeutic agent within the first 24 hours after implantation. “Initial burst” or “burst effect” or “bolus administration” refers to treatment from a drug depot within the first 24 hours when the drug depot is in contact with an aqueous fluid (eg, synovial fluid, cerebrospinal fluid, etc.). Refers to drug release. In various embodiments, the drug depot is designed to avoid this initial burst effect.

  In various embodiments, the drug depot comprises one or more different release layers (groups) that release a bolus dose of glucocorticoid or a pharmaceutically acceptable salt thereof (eg, 5 mg to 60 mg at the labeled site under the skin). ), And one or more sustained release layers (s) that release an effective amount of glucocorticoid or a pharmaceutically acceptable salt thereof over a period of time, eg, 1-8 weeks. In various embodiments, the one or more immediate release layers (s) comprise PLGA, and the immediate release layers are in one or more sustained release layers (s) comprising PLA that degrades at a lower rate than PLGA. It decomposes more rapidly than it does.

In various embodiments, when the drug depot comprises a gel, the gel can have a pre-dose viscosity in the range of about 1 to about 500 centipoise (cps), 1 to about 200 cps, or 1 to about 100 cps. After the gel is administered to the target site, the viscosity of the gel increases and the gel is about 1 × 10 ⁴ to about 6 × 10 ⁵ dynes / cm ² , or 2 × 10 ⁴ to about 5 × 10 ⁵ dynes / cm ^2. Or an elastic modulus (Young's modulus) in the range of 5 × 10 ⁴ to about 5 × 10 ⁵ dynes / cm ² .

  In one embodiment, the gel may be an adhesive gel that includes a therapeutic agent that is uniformly distributed throughout the gel. The gel may be of any suitable class as previously pointed out and should be sufficiently viscous to prevent migration of the gel from the targeted delivery site once it has been placed, Should in effect “stick” or adhere to the targeted tissue site. The gel can also be attached to the targeted tissue site not only by chemical methods, but also by mechanical interlocking with the tissue prior to curing.

  The gel can be solidified, for example, by contact with the targeted tissue or after placement from the targeted delivery system. The targeted delivery system can be, for example, a syringe, catheter, needle or cannula, or other suitable device. The targeted delivery system can inject or spray the gel into or on the targeted tissue site. The therapeutic agent can be mixed into the gel prior to placing the gel at the targeted tissue site. In various embodiments, the gel may be part of a two-component delivery system that, when mixed, activates a chemical process to form the gel and provide adhesion or adhesion to its target tissue. Turn into.

  In various embodiments, for gel formulations containing polymers, the polymer concentration can affect the rate of cure of the gel (eg, a gel with a higher polymer concentration compared to a gel with a lower polymer concentration). May solidify more rapidly). In various embodiments, as the gel hardens, the resulting matrix is solid, but is also capable of accommodating irregular surfaces of the tissue (eg, spinal recesses or processes).

  The proportion of polymer present in the gel can also affect the viscosity of the polymer composition. For example, a composition containing a polymer in a larger weight percent is generally more viscous and more viscous than a composition containing a polymer in a smaller weight percent. More viscous compositions tend to flow more slowly. Thus, in some cases, such as when the formulation is applied by spraying, a composition having a lower viscosity may be preferred.

  In various embodiments, the molecular weight of the gel can be varied by a number of methods well known in the art. The choice of method for changing the molecular weight is typically determined by the composition of the gel (eg, polymer versus non-polymer). For example, in various embodiments, when the gel contains one or more polymers, a polymerization initiator (eg, benzoyl peroxide), an organic solvent, or an activator (eg, DMPT), a crosslinker, a polymerizing agent By varying the amount and / or reaction time, the degree of polymerization can be controlled.

  Suitable gel polymers may be soluble in organic solvents. The solubility of the polymer in the solvent varies depending on the crystallinity, hydrophobicity, hydrogen bonding, and molecular weight of the polymer. Lower molecular weight polymers are usually more easily dissolved in organic solvents than higher molecular weight polymers. Polymeric gels containing high molecular weight polymers tend to aggregate or solidify more quickly than polymeric compositions containing low molecular weight polymers. Polymeric gel formulations containing high molecular weight polymers also tend to have higher solution viscosities compared to polymeric gels containing low molecular weight polymers.

  In various embodiments, the gel can have a viscosity of about 300 to about 5,000 centipoise (cp). In other embodiments, the gel has a viscosity of about 5 cps to about 300 cps, about 10 cps to about 50 cps, about 15 cps to about 75 cps at room temperature that allows the gel to be sprayed at or near the target site. be able to.

  In various embodiments, the drug depot can contain materials to increase viscosity and control drug release. Such materials include, for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylmethylcellulose, carboxymethylcellulose, and salts thereof, carbopol, poly (hydroxyethyl methacrylate), poly (methoxyethyl methacrylate), poly ( Methoxyethoxyethyl methacrylate), polymethyl methacrylate (PMMA), methyl methacrylate (MMA), gelatin, polyvinyl alcohol, propylene glycol, PEG200, PEG300, PEG400, PEG500, PEG550, PEG600, PEG700, PEG800, PEG900, PEG1000, PEG1450, PEG3350, PEG4500, PEG8000, or combinations thereof are includedFor example, in various embodiments, the drug depot contains a polymer comprising PLGA, DL-PLA, or a combination thereof, and the excipient is mPEG, D-sorbitol, maltodextrin, 10% -60% PEG3350MW. , Cyclodextrins, or combinations thereof.

  In various embodiments, the drug depot is poly (lactide-co-glycolide) (PLGA), polylactide (PLA), polyglycolide (PGA), D-lactide, D, L-lactide, L-lactide, D, L -Containing lactide- [epsilon] -caprolactone, D, L-lactide-glycolide- [epsilon] -caprolactone, glycolide-caprolactone, or combinations thereof.

  In various embodiments, the gel has an intrinsic viscosity (abbreviated as IV, unit is dL / g) that is a measure of the molecular weight and degradation time of the gel (eg, a gel with a large intrinsic viscosity is more Have a large molecular weight and a longer degradation time). Typically, high molecular weight gels provide a stronger matrix that spends more time to degrade. In contrast, low molecular weight gels break down more quickly and provide a softer matrix. In various embodiments, the gel has a molecular weight as indicated by an intrinsic viscosity of about 0.10 dL / g to about 1.2 dL / g, or about 0.10 dl / g to about 0.40 dL / g. Other IV ranges include, but are not limited to, about 0.05 to about 0.15 dL / g, about 0.10 to about 0.20 dL / g, about 0.15 to about 0.25 dL / g, About 0.20 to about 0.30 dL / g, about 0.25 to about 0.35 dL / g, about 0.30 to about 0.35 dL / g, about 0.35 to about 0.45 dL / g, about 0 .40 to about 0.45 dL / g, about 0.45 to about 0.50 dL / g, about 0.50 to about 0.70 dL / g, about 0.60 to about 0.80 dL / g, about 0.70 To about 0.90 dL / g, and about 0.80 to about 1.00 dL / g. In various embodiments, the drug depot can have an intrinsic viscosity, such as from about 0.05 to about 1.0 dL / g.

  The release profile of the drug depot can also be adjusted by, among other things, controlling the particle size distribution of the drug depot ingredients. In various embodiments, the particle size distribution of the components in the drug depot (eg, glucocorticoid, gel, etc.) is such that the drug depot can be easily delivered by injection, spraying, infusion, etc. at or near the target site. In the range of about 10 μm to 100 μm.

  In various embodiments, the drug depot can contain a hydrogel composed of a high molecular weight biocompatible elastic polymer of synthetic or natural origin. A desirable property that a hydrogel should possess is its ability to respond rapidly to mechanical stresses, particularly shear and load, in the human body.

  Hydrogels obtained from natural sources are of particular interest because they are more likely to be biodegradable and biocompatible for in vivo applications. Suitable hydrogels include, for example, natural hydrogels such as gelatin, collagen, silk, elastin, fibrin, and polysaccharide-derived polymers (such as agarose and chitosan), glucomannan gel, hyaluronic acid, polysaccharides (containing cross-linked carboxy) Polysaccharides), or combinations thereof. Synthetic hydrogels include, but are not limited to, polyvinyl alcohol, acrylamide (such as polyacrylic acid and poly (acrylonitrile-acrylic acid)), polyurethane, polyethylene glycol (eg, PEG3350, PEG4500, PEG8000), silicone, polyolefin (poly Isobutylene and polyisoprene), silicone and polyurethane copolymers, neoprene, nitrile, vulcanized rubber, poly (N-vinyl-2-pyrrolidone), acrylate (poly (2-hydroxyethyl methacrylate) and acrylate and N-vinyl pyrrolidone Copolymer), N-vinyl lactam, polyacrylonitrile, or combinations thereof. The hydrogel material can be further cross-linked to provide additional strength as required. Examples of different classes of polyurethanes include thermoplastic or thermoset polyurethanes, aliphatic or aromatic polyurethanes, polyether urethanes, polycarbonate-urethanes or silicone polyether-urethanes, or combinations thereof.

  In various embodiments, rather than mixing the therapeutic agent directly into the drug depot, the therapeutic agent (eg, glucocorticoid) can be added to the microspheres and the microspheres can be dispersed within the drug depot. . In one embodiment, the microspheres provide sustained release of the therapeutic agent. In yet another embodiment, the drug depot that is biodegradable prevents the microspheres from releasing the therapeutic agent, thus the microspheres release the therapeutic agent until they are released from the depot. do not do. For example, a drug depot can be placed around a target tissue site (eg, a nerve root). A plurality of microspheres containing the desired therapeutic agent are dispersed within the drug depot. Some of these microspheres degrade when released from the drug depot, thus releasing the therapeutic agent.

The microspheres are very similar to fluids and are distributed relatively quickly depending on the type of surrounding tissue, and thus can disperse the therapeutic agent. In some situations this may be desirable. In other cases, it may be more desirable to hold the therapeutic agent firmly in the well-defined target site.
Cannula or Needle A person skilled in the art will be able to be part of a drug delivery device such as a syringe, gun-type drug delivery device, or any medical device suitable for application of a drug to a target organ or anatomical region Alternatively, it will be appreciated that a depot can be administered to a target site (eg, at or near a herniated disc) using a needle. The cannula and needle of the drug depot device are designed to minimize physical and psychological trauma to the patient.

  Cannulas or needles have, for example, polyurethane, polyurea, polyether (amide), PEBA, thermoplastic elastomeric olefins, copolyesters, and styrenic thermoplastic elastomers, steel, aluminum, stainless steel, titanium, non-ferrous metal content Includes tubes that can be formed from materials such as metal alloys, carbon fibers, glass fibers, plastics, ceramics, or combinations thereof that are high and have a low relative proportion of iron. The cannula or needle may optionally include one or more tapered regions. In various embodiments, the cannula or needle can be cut obliquely. The cannula or needle can also have a tip style vital for precise patient treatment depending on the site of implantation. Examples of chip types include, for example, Trephine, Coulandand, Veress, Huber, Seldinger, Chiba, Francine, Bias, Crawford, curved chip, Hustad, Lancet, or Tuohey. In various embodiments, the cannula or needle can also be non-coring and have a covering over it to avoid unwanted needle sticking.

  The dimensions of the hollow cannula or needle depend on the implantation site, among other things. For example, the width of the epidural space is only about 3-5 mm in the chest region and about 5-7 mm in the lumbar region. Thus, needles or cannulas can be designed for these specific areas in various embodiments. In various embodiments, the cannula or needle is inserted, for example, along the inflamed nerve root into the spinal foramen space using a transluminal approach and a drug depot is placed at the site to treat the condition. Can be embedded in. Typically, the transforal approach involves accessing the intervertebral space through the foramen.

  Some examples of cannula or needle length include, but are not limited to, about 50-150 mm for epidural pediatric applications, eg, about 65 mm long, about 85 mm for standard adults, and for obese adult patients About 110 mm can be mentioned. The thickness of the cannula or needle also depends on the site of implantation. In various embodiments, the thickness includes, but is not limited to, about 0.05 to about 1.655. The gauge of the cannula or needle may be the maximum or minimum diameter, or a diameter in between, for insertion into the human or animal body. The maximum diameter is typically about 14 gauge and the minimum diameter is about 22 gauge. In various embodiments, the needle or cannula gauge is from about 18 to about 22 gauge.

  In various embodiments, similar to drug depots and / or gels, the cannula or needle includes a dose x-ray contrast marker that points to or near the site under the skin, so that the user can do many diagnostic imaging Any of the methods can be used to accurately place the depot at or near the site. Such image diagnostic methods include, for example, X-ray contrast or fluoroscopy. Such x-ray contrast markers include, but are not limited to, barium, calcium, and / or metal beads or particles.

  In various embodiments, the needle or cannula can include a transparent or opaque portion that can be visualized by ultrasound, fluoroscopy, x-ray or other imaging techniques. In such embodiments, the transparent or opaque portion can include a radiopaque material or ultrasound responsive topography that increases the contrast of the needle or cannula as compared to the absence of the material or topography. .

  Drug depots and / or medical devices for drug administration can be sterilized. In various embodiments, one or more components of the drug depot and / or drug delivery medical device are sterilized by radiation at the terminal sterilization stage of the final package. Product terminal sterilization provides greater assurance of sterility than by methods such as sterilization methods where individual product elements must be individually sterilized and assembled into a final package in a sterile environment.

  Typically, in various embodiments, the terminal sterilization stage uses gamma irradiation, which involves utilizing ionization energy from gamma rays that penetrate deeply into the device. Gamma rays are extremely effective at killing microorganisms, leave no remnants, and do not have enough energy to provide radioactivity to the device. Gamma radiation can be employed when the device is present in the package, and gamma sterilization does not require high pressure or vacuum conditions and thus does not stress the packaging seal and other elements. In addition, gamma irradiation does not require a permeable packaging material.

  In various embodiments, electron beam (e-beam) irradiation can be used to sterilize one or more elements of the device. E-beam irradiation generally includes a form of ionization energy characterized by low penetration and high dose rate. E-beam irradiation is similar to γ-ray treatment that changes various chemicals and molecular bonds to come into contact, including germ cells of microorganisms. The beam created for e-beam sterilization is a highly charged electron stream concentrated at one point created by charge acceleration and conversion. E-beam sterilization can be used, for example, when a drug depot is included in the gel.

  One or more elements of the depot and / or device may be sterilized using other methods including, but not limited to, gas sterilization using, for example, ethylene oxide, or steam sterilization.

In various embodiments, a kit that may include additional components (eg, ribbon-like fibers) in addition to the drug depot and / or medical device combined together for use in implanting the drug depot. Is provided. The kit can include a drug depot device in the first compartment. The second compartment can include a can that holds a drug depot and any other device required for localized drug delivery. The third compartment can include gloves, sterile cloth, wound dressings, and other treatment items to maintain the sterility of the implantation procedure, and instruction booklets. The fourth compartment can include additional cannulas and / or needles. Each instrument can be individually packaged in a plastic bag to be sterilized by irradiation. The cover of the kit can include an illustration of the method of implantation and a clear plastic cover can be placed over the compartment to maintain sterility.
Drug delivery In various embodiments, provided is a method of delivering a glucocorticoid to or near a herniated disc of a patient, the method comprising inserting a cannula into or near the herniated disc and containing the glucocorticoid The drug depot to be implanted locally in or near the herniated disc of the patient. In various embodiments, in order to administer a drug depot to a desired site, first a cannula or needle is inserted through the skin and soft tissue under the target tissue site or at or near the herniated disc and the drug depot. The agent can be administered (eg, injected, implanted, instilled, sprayed, etc.) at or near the target site. In embodiments where the drug depot is separate from the gel, a cannula or needle is first inserted under the injection site through the skin and soft tissue, and one or more sublayer (s) of the gel are inserted into the target site (eg, hernia) Vertebral disc). Following administration of one or more substrate (s), the drug depot may be embedded on or in the substrate (s) so that the gel can hold the depot in place or reduce migration. it can. If desired, a subsequent layer or group of layers of gel can be applied over the drug depot to surround the depot and further hold it in place. Alternatively, the drug depot can be first embedded and then a gel can be placed (brushed, instilled, injected, or painted) around the drug depot to hold it in place. By using the gel, accurate and precise implantation of the drug depot can be accomplished with minimal physical and psychological trauma to the patient. In various embodiments, the drug depot can be sutured to the target site, or alternatively, the drug depot can be implanted without suture. For example, in various embodiments, the drug depot can be a ribbon-shaped depot and can be placed at a target site (eg, a herniated disc) before, during, or after surgery. .

  In various embodiments, if the target site includes a spinal cord region, first a portion of the bodily fluid (eg, spinal fluid) is extracted from the target site through a cannula or needle, and then a depot is administered (placement, instillation, infusion, Or embedded). The target site is rehydrated (eg, fluid replenishment) and this aqueous environment causes the release of the drug from the depot.

“Localized” delivery includes delivery in which one or more drugs are deposited internally at or near tissue (herniated disc). For example, localized delivery includes delivery to, or very close to (eg, within about 0.1 cm to 10 cm) to nerve roots or brain regions of the nervous system. A “targeted delivery system” is a type that includes a therapeutic agent in an amount that can be deposited at or near a target tissue site (eg, a herniated disc) as required for the prevention, reduction, or treatment of herniated discs. Alternatively, delivery of a plurality of drug depots (eg, a gel, or a depot dispersed in a gel, etc.) is provided.
Intervertebral hernia Intervertebral hernia can occur anywhere in the spine, such as the cervical vertebra (neck), the thoracic vertebra (back behind the thorax), the lumbar vertebra (lumbar), and the sacral vertebra (part connected to a non-moving pelvis). In embodiments claimed in this application, the drug depot can be implanted in or near an intervertebral disc herniation, for example, in the cervical, thoracic, lumbar and / or sacral vertebrae.

  As used herein, “disc herniation” includes the local movement of disc material beyond the limits of the disc area. The intervertebral disc material can include nucleus pulposus, cartilage, fragmented apical bone, ring tissue, or any combination thereof. The movement of the disc material can cause pressure on the exiting spinal nerves and / or cause an inflammatory response that leads to radiculopathy, weakness, sensory paralysis, and / or stinging of the upper or lower limbs. Nerve root disorder refers to any disease that affects the spinal nerve roots.

  Intervertebral hernia can be caused by conditions such as sciatica, nerve compression, intervertebral back pain, spinal stenosis, nerve pinching, compression neuropathy, chronic neuralgia, sensory and / or motor neuropathy, sensory paralysis or weakness. Sometimes. Accordingly, the drug depots of the present application can be used to treat these conditions.

  In some embodiments, the herniated disc includes a rupture of annulus fibrosis, so that the intervertebral disc material (the nucleus pulposus) is extruded, protrudes, bulges, moves, and / or rehernias. Sometimes the push-out of the disc moves so that it loses continuity with the parent disc. When this happens, extrusion is called sequestration. Accordingly, the drug depots of the present application can be used to treat rupture, protrusion, bulge, extrusion, reherniaization, and migration, fragmentation and / or sequestered nucleus pulposus.

  “Migrated disc or fragmented disc” refers to the movement of disc material that exits from the opening in the annulus, which is pushed through the opening. Sometimes the moved fragments are isolated. For example, the nucleus pulposus moves out of the herniated disc and can result in the presence of isolation at various locations in the spinal column, which can lead to nerve pinching or spinal stenosis.

  In general, most disc herniation occurs in the lumbar region of the spine. Lumbar disc herniation occurs more than 15 times more than cervical disc herniation and is one of the most common causes of low back pain. The cervical disc is attacked by 8% of the number of times, and only 1-2% of the number of times in the upper to middle back (chest) disc. Sometimes herniated discs can lead to compression of the spinal nerve roots, resulting in extremely painful neurological symptoms. Nerve roots (large nerves that diverge from the spinal cord) can be compressed, resulting in neurological symptoms such as sensory or motor changes. For example, herniation of the nucleus pulposus is often accompanied by low back pain that worsens in the sitting position and pain that spreads to the lower extremities. For example, dissipative pain in sciatica is as a blunt or sharp pain with intermittent sharp electric shock sensations, sensory palsy, and stinging, movements or sensory defects in the respective nerve roots, and / or reflex abnormalities Often explained.

  In some embodiments, a glucocorticoid-containing drug depot is implanted in or near an intervertebral disc herniation where the nucleus pulposus is pushed out of the annulus and protrudes or moves so that the glucocorticoid is eluted from the drug depot. Causes enhanced nucleus pulposus resorption and reduces the size and volume of nucleus pulposus hernia. In some embodiments, the size of the nucleus pulposus is reduced and the absorption is about 15-20%, 20-25%, 25-30%, 30-35%, 35-40%, 45-50% 55-60%, 65-70%, 75-80%, 85-90%, or 95-100% increased or herniated intervertebral disc is completely resolved.

  In some embodiments, administration of glucocorticoid increases the absorption of normal spontaneous absorption of the nucleus pulposus by about 15 to more than the amount achieved by normal spontaneous absorption of nucleus pulposus not treated with glucocorticoid. 20%, 20-25%, 25-30%, 30-35%, 35-40%, 45-50%, 55-60%, 65-70%, 75-80%, 85-90%, or 95 May occur as much as ~ 100%. For example, from time to time, herniated nucleus pulposus is spontaneously absorbed by itself without treatment. This typically may take about 6-8 weeks. In some embodiments of the application, by administering the glucocorticoid to or near the intervertebral hernia, absorption of the nucleus pulposus is increased so that the hernia heals faster than without any treatment, or Increase.

  In some embodiments, the size and / or volume of the nucleus pulposus hernia is reduced to 1/5, 1/4, 1/3, 1/2, 2 / by implanting a drug depot at or near the herniated disc. Reduce to about 3, 3/4 or completely. For example, the drug depot can be implanted within the hernia 0.1 cm, 0.5 cm, 1 cm, 2 cm, 3 cm, 4 cm, 5 cm away from the herniated disc, and the size and / or volume can be within a specific time period ( 1/5, 1/4, 1/3, 1/2, 2/3, 3/4 in 3 days to 6 months, 3 days to 8 weeks, or 6 weeks to 3 months, or Fully shrink.

  In some embodiments, the closer the implanted drug depot is to the herniated disc, the greater the absorption of the nucleus pulposus, which may reduce size and / or volume, leading to improved patient condition. It was found (see Example 1). This discovery is based on the common knowledge that steroids inhibit nucleus pulposus resorption by inhibiting macrophages, fibrosis, angiogenesis, wound shrinkage, and / or altering inflammatory responses and thus inhibiting wound healing. Contrary. In contrast, Applicants have found that administering a drug depot containing a glucocorticoid (eg, fluocinolone) can increase nucleus pulposus absorption and reduce the size and / or volume of the herniated disc. ing.

  In some embodiments, the glucocorticoid reverses, reduces, and / or inhibits the progression and / or severity of disc herniation or one or more symptoms of disc herniation (eg, pain, sensory paralysis). Reduce the severity of pain (such as stinging, motor or lack of sensation).

  In some embodiments, a reduction in disc herniation (eg, due to increased nucleus pulposus absorption) can be clinically determined by improvement in the patient's symptoms or signs (eg, reduction in back pain, sensory paralysis, etc.). In some embodiments, the reduction of the herniated disc measures the size and / or volume reduction of the nucleus pulposus by diagnostic tests such as, for example, x-ray, CT, MRI, myelography, electromyogram, nerve conduction studies Can be determined.

  In some embodiments, a method for treating disc herniation in a patient in need of such treatment is provided, the method comprising one or more biodegradable drugs containing a therapeutically effective amount of glucocorticoid. Administering a depot to or near a herniated disc, wherein the one or more biodegradable drug depots are capable of releasing an effective amount of glucocorticoid for at least 3 days to 6 months .

  For exemplary purposes only, FIG. 1A shows an example of an intervertebral disc 20a. The intervertebral disc 20a is composed of two elements: the annulus fibrosus 22a and the nucleus pulposus 24a. The nucleus pulposus 24a is a gelatinous inner material surrounded by an annulus fibrosus. The nucleus pulposus distributes the mechanical load applied to the disc 20a, while the annulus 22a provides structural integrity and pushes the nucleus pulposus 24a into a particular spinal region. The annulus 22a is designed with fibrocartilaginous and fibrous tissue arranged in a concentric state called lamina. As one moves from the nucleus pulposus to the periphery, the annulus fibrosus tissue becomes denser, stronger, less elastic, less fluid, and more ligamentous until it reaches the outermost layer. Thus, the tissue is effectively a tough capsule ligament. The annulus 22a becomes weaker with age and begins to tear. As shown in FIG. 1A, a defect in the annulus called an annulus tear 22a allows for a nucleus pulposus bulge or hernia 26 at an early stage. As time progresses, the defect often leads to a complete rupture 28 of the annulus 22a and 22b, as shown in FIG. 1B. The herniated disc 20a or the ruptured disc 20b compresses the spinal canal, exerts pressure on the nerve roots passing through the discs 20a, 20b, and causes low back pain. In addition, nucleus pulposus 24a contains a significant amount of substances capable of stimulating or increasing sensory nerve excitability, such as prostaglandin E, histamine-like substances, lactic acid and polypeptide amines. These substances can leak through the ring tear 28 and intensify back pain, sciatica, or cause diffuse leg pain. In addition, ring tears 25a and 25b cause the growth of fibrous tissue during the tear, which intensifies pain and / or inflammation.

  Drug depots containing glucocorticoids can be implanted in or near hernias, such as ring ruptures or in the vicinity thereof. Implantation increases nucleus pulposus resorption and causes a reduction in hernia size and volume and / or complete resolution.

  FIG. 2 shows an intervertebral disc 30 having ring tears 34 a and 34 b in the annulus fibrosus 32. However, as a result of the drug depot implantation, at this stage, the nucleus pulposus 31 is contained and the disc is not ruptured. Drug depot 10 is delivered into the tissue adjacent to ruptures 34a and 34b (through needle 38 using plunger 37 by syringe 36). The drug depot can be injected into tissue within about 1 cm, 2 cm, or 5 cm, or 10 cm of the defect, where the depot captures the adjacent tissue 39 and the depot is a ring tear 34a and 34b. Or it can exist in the vicinity. In this manner, targeted drug delivery can be accomplished.

  In some embodiments, the closer the drug depot delivered to the hernia, the more the nucleus pulposus resorption and the smaller the herniated disc. “Reducing intervertebral hernia” refers to the number of intervertebral hernias, the degree of intervertebral hernias, the degree of intervertebral hernias compared to the number, extent, and / or severity of intervertebral hernias that occur without such administration. For example, it refers to causing a reduction in area) and / or severity of disc herniation (eg, thickness, volume). In various embodiments, reducing a herniated disc is part of the protocol and can further include performing a procedure (eg, a subsequent operation to reduce the herniated disc). The composition or treatment may prevent the formation of a herniated disc following stimulation that promotes the herniated disc, may prevent the progression of the herniated disc, and / or may prevent recurrence of the herniated disc There is.

  “Preventing a herniated disc” refers to administering a therapeutic composition prior to the formation of a herniated disc to reduce the likelihood of an herniated disc in response to a particular injury, irritation, or condition. Point to. In various embodiments, preventing a herniated disc is part of the protocol and can further include performing a procedure (eg, surgery to reduce the herniated disc). “Preventing disc herniation” does not require reducing the possibility of disc herniation to zero. Rather, “preventing disc herniation” is a clinically significant reduction in the probability of disc herniation following a specific injury or stimulation, eg, a specific injury, condition, or that promotes disc herniation, or Refers to a clinically significant reduction in the incidence or number of disc herniation in response to a stimulus.

  “Treatment of a herniated disc” reverses (completely or partially), reduces, reduces, and / or prevents the progression and / or severity of a herniated disc, or the likelihood of recurrent disc herniation. And / or administration of a composition that reduces severity. “Treatment of a herniated disc” also refers to reversing, reducing, reducing, preventing or preventing the progression of one or more symptoms of disc herniation (eg, pain, tingling, sciatica). Refers to reducing the likelihood and / or severity of relapse. In various embodiments, treating a herniated disc is part of the protocol and can further include performing a procedure (eg, surgery to reduce the herniated disc). Thus, “treating an intervertebral hernia” includes applying a therapeutic composition and / or treatment as soon as an intervertebral hernia (s) has already been formed following injury or irritation.

  The term “pain” includes pain nociception and sensation, both of which can be objectively and subjectively evaluated using pain scores and other methods well known in the art. it can. Typical types of pain that can be reduced, prevented or treated by the methods and compositions disclosed herein include, but are not limited to, back pain, neck pain, leg pain, root pain, neuropathic pain (upper limb , Cervical, back, lumbar, lower limb), or related pain distributions derived from disc or spine surgery.

  Although a spinal site is shown, as noted above, the drug depot is not limited to, but is limited to, at least one muscle, ligament, tendon, cartilage, spinal disc, spinal space, near spinal nerve root, or It can be delivered to any site under the skin, including the spinal canal. In various embodiments, a drug depot containing glucocorticoid can be administered parenterally to a patient. The term “parenteral” as used herein refers to a mode of administration that bypasses the gastrointestinal tract, for example, localized intravenous, intramuscular, continuous or intermittent defect, intraperitoneal, intrasternal, subcutaneous. Intraoperative, intrathecal, intravertebral, perivertebral, epidural, perivertebral, intraarticular injection, or a combination thereof.

  Parenteral administration can also be inserted at or near the infusion pump, target site, for example, locally administering a pharmaceutical composition (eg, glucocorticoid) through a catheter in the vicinity of the spine or one or more inflammatory joints An implantable minipump, an implantable controlled release device or sustained release delivery system capable of releasing a constant amount of composition per hour in continuous or intermittent bolus doses can be included. One example of a pump suitable for use is the SynchroMed® pump (Medtronic, Minneapolis, MN). This pump has three sealed chambers. One houses an electronic module and a battery. The second chamber houses a peristaltic pump and a drug reservoir. The third chamber contains an inert gas that provides the pressure necessary to push the pharmaceutical composition into the peristaltic pump. To deliver to the pump, the pharmaceutical composition is injected into the inflatable reservoir through the reservoir fill port. The inert gas applies pressure to the reservoir, which forces the pharmaceutical composition through the filter and into the pump chamber. The pharmaceutical composition is then pumped from a device in the pump chamber into a catheter directed to deposition at the target site. The delivery rate of the pharmaceutical composition is controlled by the microprocessor. This allows the pump to be used to deliver the same or different amounts of the pharmaceutical composition continuously for a fixed time or set delivery interval.

  Drug delivery devices that may be suitable for adaptation to the methods described herein include, but are not limited to, for example, medical catheters for target-specific drug delivery. US Pat. No. 6,551,290 (assigned to Medtronic, the entire disclosure of which is incorporated herein by reference), describes an implantable medical device for controllable release of biologically active agents. US Pat. No. 6,571,125 described (assigned to Medtronic, the entire disclosure of which is incorporated herein by reference), within the substance for delivering a therapeutic agent to a selected site in an organism. US Pat. No. 6,594,880 describing an infusion catheter system (assigned to Medtronic, the entire disclosure of which is incorporated herein by reference) US Pat. No. 5,752,930 (assigned to Medtronic, which describes an implantable catheter for instilling an equal volume of drug at spaced sites, the entire disclosure of which is hereby incorporated by reference. The device as described in the above). In various embodiments, the pump is a pre-programmable implantable device with feedback-controlled delivery, a micro-reservoir osmotic release system for controlled release of chemicals, and a compact for delivering liquid medications It can be constructed using a light weight device, an implantable micro-infusion device, an implantable ceramic valve pump assembly, or an implantable infusion pump with a folding fluid chamber. Alzet® osmotic pumps (Durec, Cupertino, Calif.) Are also available in a variety of sizes, pump flow rates, and durations suitable for use with the described methods. In various embodiments, a method for delivering a therapeutic agent to a patient's surgical site is provided. For example, implantable Alzet® osmotic pumps deliver steroids locally to the target tissue site essentially continuously (eg, Alzet® osmotic pumps are proximate to the sciatic nerve). Allows continuous infusion delivery of glucocorticoids in micrograms / hour within the sheath.

  In various embodiments, since the glucocorticoid is administered locally, the therapeutically effective dose may be less than the dose administered by other routes (oral, topical, etc.). For example, drug doses delivered from drug depots are, for example, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% of oral or injectable doses. %, 95%, 99%, or less than 99.9%. If the viewpoint is changed, systemic side effects such as hepatic transaminase elevation, hepatitis, renal failure, myopathy, constipation, and the like can be reduced or eliminated.

The term “patient” is derived from the taxonomic category “mammal” including but not limited to humans, other primates (such as chimpanzees, ape orangutans and monkeys), rats, mice, cats, dogs, cows, horses, etc. Refers to the organisms.
Methods of preparing glucocorticoid depots In various embodiments, a drug depot containing a glucocorticoid combines a biocompatible polymer with a therapeutically effective amount of glucocorticoid or a pharmaceutically acceptable salt thereof, and the combination Can be prepared by forming an implantable drug depot.

  Various techniques, including solution processing techniques and / or thermoplastic processing techniques, may be used to form at least a portion of the drug depot from the biocompatible polymer (s), therapeutic agent (s), and optional materials. Available. When using solution processing techniques, typically a solvent system is selected that includes one or more solvent species. The solvent system is generally a good solvent for at least one important component, such as a biocompatible polymer and / or therapeutic agent. The individual solvent species that make up the solvent system can also be selected based on other properties, including drying rate and surface tension.

  Solution processing techniques include solvent casting techniques, spin coating techniques, web coating techniques, solvent spraying techniques, dipping techniques, techniques involving coating via mechanical suspension including air suspension (eg fluidized coating), Inkjet technology and electrostatic technology are included. If appropriate, techniques such as those listed above can be repeated or combined to construct a depot to obtain the desired release rate and desired thickness.

  In various embodiments, a solution containing a solvent and a biocompatible polymer can be combined and poured into a mold having a desired size and shape. In this manner, a polymer region including a barrier layer, a lubricating layer, and the like can be formed. If desired, the solution may further dissolve or disperse one or more of the following: glucocorticoids and other therapeutic agent (s), and any other additives such as X-ray contrast agent (s). Can be included. This produces a polymer matrix region containing these species after removal of the solvent. In other embodiments, a solution containing a solvent with a dissolved or dispersed therapeutic agent can be formed using a variety of techniques, including solution processing techniques and thermoplastic processing techniques, pre-existing polymer regions. Where the therapeutic agent is absorbed into the polymer region.

  Thermoplastic processing techniques to form a depot or part thereof include molding techniques (eg, injection molding, rotational molding, etc.), extrusion techniques (eg, extrusion, co-extrusion, multilayer extrusion, etc.) and casting Is included.

  The thermoplastic processing according to various embodiments may include one or more of biocompatible biopolymer (s) and the following: glucocorticoid, optional additional therapeutic agent (s), x-ray contrast agent (s), etc. Including mixing or blending in one or more stages. The resulting mixture is then molded into an implantable drug depot. The mixing and molding operations can be performed using any conventional equipment known in the art for such purposes.

  During thermoplastic processing, there is a potential for the therapeutic agent (s) to degrade due to, for example, the temperature rise and / or mechanical shear associated with such processing. For example, glucocorticoid tromethamine can undergo significant degradation under normal thermoplastic processing conditions. Therefore, the processing is preferably performed under relaxed conditions that prevent significant degradation of the therapeutic agent (s). While it is understood that some degradation during the thermoplastic processing may be unavoidable, degradation is generally limited to 10% or less. Among the processing conditions that can be controlled during processing to avoid significant degradation of the therapeutic agent (s) are temperature, applied shear rate, applied shear stress, residence time of the mixture containing the therapeutic agent, and polymeric materials and There are techniques for mixing therapeutic agents (groups).

  It is well known in the art to mix or blend the biocompatible polymer with the therapeutic agent (s) and any additional additives to form a substantially homogeneous mixture thereof and the polymeric material It can be carried out using any apparatus commonly used for mixing with additives.

  When employing thermoplastic materials, the polymer melt is formed by heating a biocompatible polymer that can be mixed with various additives (eg, therapeutic agent (s), inert ingredients, etc.) to form a mixture. Can do. Therefore, a common practice is to apply mechanical shear to the mixture of biocompatible polymer (s) and additive (s). Equipment that can mix biocompatible polymer (s) and additive (s) in this manner includes single screw extruder, twin screw extruder, Banbury mixer, high speed mixer, loss kettle, etc. It is.

  The final thermoplastic mixing and molding process, if desired, any of the biocompatible polymer (s) and various additives (for example, to prevent significant degradation of the therapeutic agent, among other reasons) Prior to premixing.

  For example, in various embodiments, the biocompatible polymer is pre-blended with an x-ray contrast agent (eg, a radioopaque agent) under conditions of temperature and mechanical shear that, if present, result in significant degradation of the therapeutic agent. . This pre-blended material is then mixed with a therapeutic agent under conditions of lower temperature and mechanical shear, and the resulting mixture is formed into a drug depot containing glucocorticoid. Conversely, in another embodiment, the biocompatible polymer can be pre-blended with the therapeutic agent under conditions of reduced temperature and mechanical shear. This pre-blended material is then mixed with, for example, a radiation opacifier, also under reduced temperature and mechanical shear conditions, and the resulting mixture is cast into a drug depot.

  The conditions used to achieve the mixing of the biocompatible polymer, therapeutic agent, and other additives are, for example, the specific biocompatible polymer (s) and additive (s) used and the use It depends on several factors including the type of mixing device being used.

  As an example, various biocompatible polymers are typically softened at various temperatures to facilitate mixing. For example, a depot is formed containing a PLGA or PLA polymer, a radiation opacifier (eg, bismuth subcarbonate), and a therapeutic agent (eg, glucocorticoid) that tends to degrade with heat and / or mechanical shear. In various cases, in various embodiments, PGLA or PLA can be premixed with a radiation opacifier, for example, at a temperature of about 150 ° C to 170 ° C. The therapeutic agent is then combined with the premixed composition and subjected to further thermoplastic processing at conditions of substantially lower temperature and mechanical shear than is typical for PGLA or PLA compositions. For example, when using an extruder, barrel temperature, volumetric extrusion rate is typically controlled to limit shear and thus prevent significant degradation of the therapeutic agent (s). For example, therapeutic agents and pre-mixed compositions can be used with a twin screw extruder at substantially lower temperatures (eg, 100-105 ° C.) and substantially reduced volume extrusion (eg, generally , Corresponding to a volume extrusion rate of less than 200 cc / min, less than 30% of maximum capacity). Note that this processing temperature is well below the melting point of glucocorticoids, as processing at or above these temperatures results in significant degradation of the therapeutic agent. Furthermore, it should be noted that in some embodiments, the processing temperature is below the melting point of all bioactive compounds in the composition, including the therapeutic agent. After compounding, the resulting depot is cast into the desired shape, also under reduced temperature and shear conditions.

  In other embodiments, the biodegradable polymer (s) and one or more therapeutic agents are premixed using non-thermoplastic techniques. For example, the biocompatible polymer can be dissolved in a solvent system that includes one or more solvent species. Any desired agent (eg, a radioopaque agent, a therapeutic agent, or both a radioopaque agent and a therapeutic agent) can also be dissolved or dispersed in a solvent system. The solvent is then removed from the resulting solution / dispersion to form a solid material. The resulting solid material can then be granulated for further thermoplastic processing (eg, extrusion) if desired.

  As another example, a therapeutic agent can be dissolved or dispersed in a solvent system and then applied to a pre-existing drug depot (the pre-existing drug depot is a solution and thermoplastic processing treatment). And can include various additives including radioopaque agents and / or thickeners), where the therapeutic agent Is absorbed on or in the drug depot. The resulting solid material can then be granulated for further processing if desired, as described above.

  Typically, extrusion methods can be used to form drug depots containing biocompatible polymer (s), therapeutic agent (s), and a radioopaque agent. For producing a drug depot with the same or different layers or regions (eg, a structure comprising one or more polymer matrices or regions with fluid permeability allowing immediate and / or sustained drug release) Co-extrusion, which is a molding method that can be used for, can also be employed. Multi-region depots can also be formed by other processing and molding techniques such as co-injection or sequential injection molding techniques.

  In various embodiments, depots (eg, ribbons, pellets, strips, etc.) that can come out of the thermoplastic processing are cooled. Examples of the cooling process include air cooling and / or immersion in a cooling bath. In some embodiments, the extruded depot is cooled using a water bath. However, when using water soluble drugs such as glucocorticoids, soaking time should be kept to a minimum to avoid unnecessary loss of therapeutic agent into the bath.

  In various embodiments, immediate removal of water or moisture by using a jet of ambient or warm air after leaving the bath also prevents recrystallization of the drug at the depot surface, Thus, high drug dose “initial burst” or “bolus administration” by implantation or insertion is controlled or minimized if this release profile is not desired.

  In various embodiments, the drug depot can be prepared by mixing or spraying the drug with the polymer and then shaping the depot into the desired shape. In various embodiments, glucocorticoids can be used, mixed with or sprayed onto the polymer, and the resulting depot formed by extrusion and dried.

Having generally described the invention so far, the same will be more readily understood through the following reference to the following examples. The examples are provided by way of illustration and are not to be construed as limiting the invention unless otherwise specified.
Example

Objective: To determine the effect of fluocinolone-eluting PLA polymer pellets on NP absorption Summary: The nucleus pulposus was collected from the coccyx (tail) disc of female Sprague-Dawley rats, 15 donors, and 15 recipients One female Sprague-Dawley rat was implanted into the abdominal subcutaneous space. NPs from the eight coccyx discs of each donor rat were combined into one aggregate for transplantation (one NP aggregate per recipient). Fifteen recipients were randomly divided into 3 groups. One group received 0.88 wt% fluocinolone pellets (containing 10 wt% PEG1500 in 100DL PLA5E, length 2.0 mm x diameter 0.5 mm) in the same subcutaneous pocket as the NP implant. The second group received identical fluocinolone (Flu) pellets in a separate subcutaneous pocket 1.5 cm (from end to end) from the pocket containing the NP. The last group received a control PLA pellet in another 1.5 cm subcutaneous pocket from the pocket containing the NP. The Flu pellet used in this study is expected to elute approximately 0.01 μg / day fluocinolone according to in vitro data. Approximately 72 hours after surgical placement of NPs and pellets, animals were humanely euthanized by CO ₂ asphyxiation and NPs from 4 animals belonging to each of the three groups were evaluated to assess NP absorption. Explanted. For histological analysis, one animal belonging to each of the three groups was randomly selected. The mass% of the ectopic NP remaining at the end point was used as an index of the absorption rate.

Results and conclusions: Apparent NP absorption tended to be higher in animals that received fluocinolone pellets. This finding was contrary to our previous research hypothesis (ie, fluocinolone may block NP absorption). The percentage of ectopic NP remaining on the third day was 20.78 ± 5.25% in the group where the Flu pellet was placed in the same pocket as the NP, and the Flu pellet was placed 1.5 cm away from the NP. It was 32.38 ± 5.71% in the group and 40.00 ± 5.33% in the control pellet group. The number of animals in each group was too small to draw a definitive conclusion, but a theoretical comparison was made between the control group and the same pocket Flu group. The difference between these two groups reached statistical significance when compared in isolation (p = 0.04). The overall histological findings are consistent with the well-known effects of fluocinolone on inflammation. That is, animals subjected to histological examination from the same pocket Flu group had a reduced inflammatory response compared to the control pellet group. This assessment includes the size of the inflammatory pseudocapsule and the number of non-macrophage inflammatory cells inside or adjacent to the capsule. The group with the Flu pellet placed in another pocket had an intermediate inflammatory response. However, the number of macrophages in residual NP appeared to be increased in animals that received the Flu pellet (more so in animals that received the Flu pellet in the same pocket as the NP). This strange finding suggests that macrophage activity may be responsible for the increased NP absorption rate in animals that received the Flu pellet. However, the inverse relationship between overall inflammatory response and macrophage activity cannot be explained by available data. Further, a section of a 1.5 cm pocket on the opposite side of the NP pocket was examined histologically. Histological findings in these secondary pockets were consistent with normal wound healing and did not appear to be affected by Flu or control pellets (when compared to pseudo incisions). Fluocinolone was not detectable in the plasma of any animal (LLD 0.05 ng / mL).
(Details of Example 1)
Fluocinolone is a corticosteroid with anti-inflammatory properties, and this study was intended to explore these properties with the ultimate goal of understanding the role of fluocinolone in the healing of intervertebral hernia. The natural history of isolated herniated nucleus pulposus after disc herniation is partial or complete absorption over the course of 3-6 months. It was hypothesized that fluocinolone could reduce NP (nuclear nucleus) absorption by disrupting the immune inflammatory response that is believed to be responsible for this absorption process. In a recent study, the effect on the NP absorption rate of subcutaneous pellet implants releasing fluocinolone was evaluated (compared to control pellets). This effect was evaluated in a pilot study using 1) the weight of NP recovered 3 days after transplantation, and 2) histopathological assessment of the tissues surrounding both pockets in a sub-population of animals. NPs were removed from the eight tail discs of donor rats and implanted into the recipient rat's subcutaneous pocket. Treatment groups included animals with fluocinolone releasing pellets embedded in the same pocket as NP or in a far (1.5 cm apart) pocket to assess fluocinolone penetrance. One group was embedded with a control pellet. The pellet was collected at the time of necropsy. The pellet was expected to be stable over the course of 72 hours. The pellets were durable for months and were designed to disintegrate after 4-6 months. Results from this study showed that fluocinolone pellets, when present with NP in the same pocket, tend to increase absorption after 3 days of implantation. In contrast, absorption was reduced when the control pellet was in another pocket located 1.5 cm from the NP pocket. The group of animals with the fluocinolone pellet in the far pocket showed intermediate results for the% of NP remaining after 3 days. The histological findings appear to correlate with these results, and when fluocinolone is present together in the same pocket, the minimal amount of inflammatory infiltrate surrounding NP is reduced in animals implanted with control pellets. With the greatest amount of inflammatory response.
Experimental Procedure Animals This study included a total of up to 34 female Sprague-Dawley rats. Thirty animals were used for the study and four rats were utilized to meet the reserve requirements. Rats did not have a specific pathogen and weighed approximately 200 g on the day they arrived in the incubator.
Acceptance, Health Assessment and Acclimatization Upon acceptance, rats were removed and placed in cages. For each animal, a visual health check was performed for abnormal signs of posture and movement, including the coat, limbs, and open mouth assessment. None of the rats found any abnormalities. Rats were acclimated for approximately one week prior to beginning surgery.
Environment Rats were housed in cages in transparent polycarbonate plastic cages. The bedding material was irradiated corn cob bedding (Enrich-O-Cob, The Andersons, Maumee, OH) that was exchanged as often as needed to provide the animal with dry bedding. The study record details the room number in which the rat is housed from the beginning to the end of the study period. The room was supplied with air filtered with HEPA. The room was on a 12 hour light / dark cycle (bright hours are approximately 6:00 to 18:00).
Diet and water Animals had free access to a pelleted diet (Certified Pico). The manufacturer provided a certificate of analysis detailing the levels and / or concentrations of specific heavy metals, aflatoxins, organophosphates, and specific nutrients for each batch of diet. The analysis certificate (CA) was saved.

  From the beginning to the end of the study period, animals had free access to deionized water. Water analysis was performed twice a year and the CA on water analysis, including analysis of heavy metals and dissolved minerals, continued to be preserved.

There were no known ingredients in food or water that interfered with the purpose or operation of this study.
Cage and Animal Identification Each animal was assigned an identification number corresponding to a sequentially numbered ear tag. Prior to assignment of animals to treatment groups, cages were identified with the following information: study number, species / strain, sex, cage number and ear tag number. Cage identification did not change after assignment to treatment group.
Group treatment Fifteen recipients were randomly divided into three groups (see Table 1). One group (n = 5) made an additional incision and tunnel placed 1.5 cm lateral to match the conditions of the other group, but fluocinolone in the same subcutaneous pocket where the NP was placed An eluting 100DL5E pellet (FLU) was received (FLU-0 cm). The 100DL5E pellet was a 1 mm long x 0.7 mm diameter cylinder designed to be stable in vivo for over 60 days. The second group (n = 5) received FLU (FLU-1 cm) in another subcutaneous pocket 1.5 cm transverse (to the left of the animal) to the pocket where the NP was placed. The last group received a control pellet in the subcutaneous pocket 1.5 cm transverse (left) to the pocket in which the NP was placed (control). The subject 100DL5E pellet did not elute fluocinolone or any active drug.

Body weight and clinical observation Body weight was measured prior to surgery. In addition, animals were regularly observed for signs of illness / health.
Rats for surgery NP collection of NP donor rats were humanely sacrificed with a lethal dose of CO _2. The tail was removed from the donor rat and NP was extracted from each intervertebral disc. NPs were removed from a total of 8 intervertebral discs from a single donor rat, combined together for a single implant, and weighed. The combined NPs were kept in a moist environment (gauze soaked in saline) to prevent drying.
Surgery of NP recipient rats Once NPs were collected from donor rats, the recipient rats were placed under isoflurane anesthesia. A small incision approximately 2 cm in length was made in the abdominal skin approximately 1.5 cm to the left of the sagittal midline near the recipient rat's axial midline, and a subcutaneous tunnel was made with hemostatic forceps. The NP was placed in the SC pocket. The incision site was sewn with continuous sutures using vicryl 4-O suture. In all groups, a similar second incision was made on the right side of the rat, opposite the first pocket. In this pocket, a fluocinolone pellet (Group 2) or a control pellet (Group 3) was placed, or none (Group 1). Each implant site was marked with a skin tattoo. The tunnel to the pocket was a parallel path with pocket edges about 1.5 cm from each other.
Collection of terminal blood Blood samples (at least 1.5 mL) were obtained from all animals by cardiac puncture. Prior to collection, the animals were anesthetized with isoflurane. Blood samples were collected in K2EDTA tubes and immediately placed on ice water. Blood samples were centrifuged within 1 hour of collection and plasma (at least 500 μL) was removed and stored in a −20 ° C. freezer until shipped by dry ice to a laboratory listed below for analysis. The 13 specimens were shipped within 7 business days after collection (2 specimens were excluded because they coagulated).
Euthanasia Three days after NP transplantation, animals were humanely euthanized by CO ₂ asphyxiation.
NP recovery NP was collected from 4 animals per group (n = 12) and weighed. Briefly, the tattoo marking the surgical site where the NP was placed was identified. The overlying skin was opened and exposed to any residual NP. The NP was removed and placed directly into the weighing boat. If there were pellets in the same pocket with the NP, the pellet was removed before weighing.
Tissue collection for histology For histological evaluation, tissues surrounding implants and NPs were collected from one animal randomly selected per treatment group (n = 3). A tissue region (body wall, subcutaneous tissue and skin) containing both the implant site and approximately 1 cm of tissue surrounding the implant site was collected as one specimen. The specimen was placed on a flat surface and then immersed in 10% neutral buffered formalin within 15 minutes of euthanasia to allow fixation.
Histology Once fixed, the tissue specimens are subjected to a single section through the adjacent implant or pseudo-implant site, and three sections (sections through the NP or NP + implant site, depending on the treatment group). The shape was arranged in such a way as to obtain (4-5 mm) and two side sections). Tissues were processed, embedded in paraffin, sectioned and stained with H & E. A veterinary pathologist read the slide and assessed the extent of the inflammatory response and residual NP.
Results The weight of transplanted and removed NPs is shown in Table 2. The percent remaining NP was calculated for each animal and averaged for each treatment group. These data are represented graphically in FIG. 3 and statistical analysis (one-way ANOVA) was calculated. There appeared to be a tendency to show that fluocinolone can lead to a reduction in the amount of NP remaining in the pocket after 3 days. A correlation analysis evaluating the relationship between the amount of transplanted NP and the ratio of recovered NP appeared to indicate that there was a trend for an inverse relationship (Pearson's r = 0.48). Records from the surgeon indicated that for almost all animals, the NP consistency was greater when removed than at the time of implantation.
Discussion The results from this study showed that the presence of fluocinolone pellets with NP in the same pocket tends to increase absorption 3 days after implantation. In contrast, absorption was reduced when the control pellet was in another pocket located 1.5 cm from the NP pocket. Groups of animals with fluocinolone pellets in remote pockets showed intermediate results with respect to the percent of NP remaining after 3 days. The histological findings appear to correlate with these results, and when fluocinolone is present together in the same pocket, the minimal amount of inflammatory infiltrate surrounding NP is reduced in animals implanted with control pellets. With the greatest amount of inflammatory response.

  Table 2 shows the autopsy information of the different treatment groups (TG) shown in the table below, as judged from the NP.

Fluocinolone formulation and release profile Fluocinolone is a potent steroid with glucocorticoid activity. In order to obtain a reliable release, a fluocinolone drug depot was prepared as follows. The drug depot includes 0.88 wt% fluocinolone, 10 wt% PEG 1500, and 88.22 wt% 100DL5E.

Fluocinolone formulation and release profile Fluocinolone is a potent steroid with glucocorticoid activity. In order to obtain a reliable release, a fluocinolone drug depot was prepared as follows. The drug depot contained 0.88 wt% fluocinolone, 10 wt% PEG 1500, and 88.22 wt% 100DL5E (with ester end groups). The abbreviation “DL” refers to poly (DL-lactide). The drug depot had an average pellet diameter of 0.5 mm and the average pellet length was 2.02 mm.

  One skilled in the art will appreciate that other polymers can be used in this application. For example, 85/15 PLGA or DL-PLA or DL-PLA, and 50/50 PLGA mixture can be added in an amount of about 10% to 99% with 1% fluorocinolone loading. In this study, the average pellet diameter was 0.5 mm and the average pellet length was 2.02 mm, but other depots can be prepared by extruding to different sizes (eg, 0.75 (Length) × 0.75 mm (diameter), 0.8 × 0.8 mm, 1 × 1 mm pellet size, etc.).

  For polymers used in depots, if the polymer is a heteropolymer or copolymer, a mixture of monomer species is often present in the polymer.

Claims (15)

  A method of treating intervertebral hernia in a patient in need of such treatment, comprising administering one or more biodegradable drug depots containing a therapeutically effective amount of glucocorticoid to or near the intervertebral hernia. And wherein the one or more biodegradable drug depots are capable of releasing an effective amount of a glucocorticoid over a period of at least 3 days to 6 months.   The one or more drug depots reduce the size of the hernia by at least 20% by increasing absorption of the nucleus pulposus when the one or more drug depots are implanted within 5 cm of the hernia. Item 2. The method according to Item 1.   The method of claim 1, wherein the one or more drug depots reduce hernia size by at least 50% by increasing absorption of the nucleus pulposus.   The method of claim 1, wherein the glucocorticoid comprises fluocinolone or dexamethasone.   5. The method of claim 4, wherein the one or more drug depots release an effective amount of fluocinolone or dexamethasone over a period of at least 3 days to 6 weeks.   6. The method of claim 5, wherein the one or more drug depots release 0.002 μg to 0.02 μg fluocinolone every 24 hours for at least 1 to 6 weeks.   2. The one or more drug depots added with a glucocorticoid in an amount of about 0.5% to about 40% by weight, based on the total weight of the drug depot. Method.   The method of claim 1, wherein the one or more drug depots are administered to the herniated disc before, during, or after surgery.   2. The method of claim 1, wherein the barrier is administered at or near the disc herniation before, after, or concurrently with the administration of one or more drug depots.   The method of claim 1, wherein the glucocorticoid comprises fluocinolone acetonide, fluocinonide, dexamethasone, dexamethasone sodium phosphate, dexamethasone acetate, or a pharmaceutically acceptable salt thereof, or a combination thereof.   Glucocorticoid is cortisone, hydrocortisone, prednisone, prednisolone, methylprednisolone, budesonide, dexamethasone, fludrocortisone, fluocortron, clopredonol, deflazacort, triamcinolone, or a pharmaceutically acceptable salt thereof, or a combination thereof The method of claim 1 comprising:   The drug depot is poly (lactide-co-glycolide) (PLGA), polylactide (PLA), polyglycolide (PGA), D-lactide, D, L-lactide, L-lactide, D, L-lactide-caprolactone, The method of claim 1, comprising a polymer comprising D, L-lactide-glycolide-caprolactone, or a combination thereof.   An implantable drug depot useful for treating intervertebral hernia in a patient in need of such treatment, wherein the implantable drug depot contains a therapeutically effective amount of glucocorticoid, The agent can be implanted at or near an intervertebral hernia, the drug depot is supplemented with about 0.5% to about 40% by weight glucocorticoid, and an effective amount of glucocorticoid for at least 3 days to 8 weeks Implantable drug depot with the ability to release   17. The implantable according to claim 16, wherein the drug depot contains fluocinolone acetonide, fluocinonide, dexamethasone, dexamethasone sodium phosphate, dexamethasone acetate, or a pharmaceutically acceptable salt thereof, or a combination thereof. Drug depot.   A method of reducing the size of an intervertebral hernia in a patient comprising administering one or more biodegradable drug depots containing fluocinolone to or near the intervertebral hernia. A method wherein the degradable drug depot is capable of releasing fluocinolone for at least 3 days to 2 months to reduce the size of the disc herniation by at least 50%.

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