Pharmaceutical composition comprising microparticles for high drug loading

Abstract

The present document describes a pharmaceutical composition comprising a plurality of microparticles loaded with a positively charged drug, the microparticles comprising cross-linked molecules of a polyhydroxylic polymer comprising hydroxyl groups and having anionic functional groups comprising carboxylic, phosphate, metaphosphate, or sulfonate functional groups, or combinations thereof. The anionic functional groups are providing a negative charge to the microparticles, and interacting ionically with said positively charged drug. The cross-linked molecules of a polyhydroxylic polymer have a degree of substitution of hydroxyl groups of about 0.1 to about 1.5, and an exchange capacity of from about 0.1 to 2.76 mEq of the anionic functional groups per mL of cross-linked molecules of a polyhydroxylic polymer, and they are operable to provide a size distribution of about 45 µm to 1200 µm.

Description

PHARMACEUTICAL COMPOSITION COMPRISING MICROPARTICLES FOR HIGH DRUGLOADINGCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority of US provisional patent application No. 63 / 568,030, filed on March 21st, 2024, and US provisional patent application No. 63 / 569,356, filed on March 25th, 2024, the specifications of which are hereby incorporated by reference in their entireties.BACKGROUND(a) Field

[0002] The disclosed subject matter generally relates to a pharmaceutical composition comprising microparticles for high drug loading, methods for vascularembolization, radio-embolization, or both, of a blood vessel, such as an artery, with the pharmaceutical composition and methods for the management of pain during vascular embolization, radio-embolization, or both, of a blood vessel.(b) Related Prior Art

[0003] Uterine fibroids are a very common condition which consists in the presence of benign tumors in the uterus.

[0004] Uterine Fibroid Embolization (UFE), also known as Uterine artery embolization (UAE ) is a less invasive alternative to hysterectomy to treat symptomatic uterine fibroids (Keung et al, 2018, Hehenkamp et al, 2006). UFE generates substantial pain which starts immediately after the embolization, peaks at about 7 hours later and gradually decreases within the next few days. Pain intensity during the first 24 hours is often not well controlled despite large doses of narcotics that are associated with side effects, and frequently requires overnight hospitalization. Other analgesic methods, such as hypogastric nerve bloc and epidural anesthesia, have demonstrated some effectiveness to alleviate UFE-induced pain, but these methods prolong the intervention, require additional resources, are not always effective or do not last long enough. Hence, there remains an unmet need for an effective analgesic method allowing painless outpatient UFE without invasive anesthetic interventions.

[0005] Ischemic pain can be alleviated by intra-arterial lidocaine injection after UFE (Duvnjak and Andersen, 2020) or liver chemoembolization. However, post-UFE pain relief reported with 200 mg of intra-arterial lidocaine was short lived due to the short half-life (2-3 h) of lidocaine and to the quick wash out of a single lidocaine injection. Consequently, prolonged post-UFE pain relief after a single intra-arterial injection would require a larger amount of lidocaine with a delayed drug delivery mechanism.

[0006] Drug eluting beads (DEB) are an effective way to carry chemotherapeutic drugs to treat liver cancer. Drug loading and elution characteristics and pharmacokinetics have demonstrated a slower drug release and lower plasmatic peak concentration of the drug, enhancing their safety (Guiu et al, 2015). Thus, DEB seem to be an appealing method for sustained lidocaine delivery after UFE.

[0007] Cross-linked high amylose starch (HAS-CL) with epichlorohydrin (a non-ionic crosslinker) as tablet-form devices loaded with ciprofloxacin have been proposed for long-lasting implants in the treatment of osteomyelitis (Desevaux et al, 2002). The High Amylose starch is a type of starch with a high amylose content (about 70 %). This material and its use are different to those proposed by this disclosure.

[0008] Transarterial embolization is a minimally-invasive treatment of solid tumors. Crosslinked starch microspheres slowly-biodegradable by serum a-amylase, known as Degradable Starch Microspheres (DSM) or Spherex® have been described as candidates for clinical translation (Gross et al, 2020). The cross-linking was done with non-ionic epichlorohydrin and the microspheres cannot be ionically loaded with cationic bioactive materials, because lack of anionic groups.

[0009] Lidocaine has a cationic form and could be loaded by ion-interaction onto anionic DEB ( / .e. DCBead™). The drug carrying capacity of these DEB is generally provided by the sulphonated modification of polyvinyl alcohol (PVA) generating anionic sites. Generally, for ion-exchange DEB, theoretical maximum loading capacity for every mL of DEB can be calculated as equivalent of drug that is ionically bound per number of sulfonate groups in the DEB. For example, in one mL of DC Bead™ (from Boston Scientific), 7.7 xIO’5mol of negatively charged sulfonate groups are available for carrying protonated drug indicating that DC Bead™ can load up to 18 mg of lidocaine for every mL of DEB (Taylor et al, 2007). The large amount of lidocaine (>200 mg) that could be needed for sustained analgesic effect after UFE would require a higher loading capacity than those of current commercially available DEB.

[0010] Enhanced carrying capacity can be provided by the increased number of anionic sites of materials treated with sodium trimetaphosphate (STMP): modified PVA (CLPVA-MP), starch crosslinked with STMP (CLS-MP) or carboxymethylated starch (CMS) or CMS cross-linked with STMP (CLCMS-MP), where MP stands for metaphosphate anion. These compounds are biocompatible materials that could offer the desired increases in anionic binding sites. The hypothesis is that CLPVA- MP, CLS-MP, CMS or CLCMS-MP would substantially improve lidocaine loading in comparison with the known PVA DEB. This improved lidocaine loading would allow for effective sustained pain relief after UFE.SUMMARY

[0011] According to an embodiment, there is provided a pharmaceutical composition comprising: a plurality of microparticles loaded with a positively charged drug, said microparticles comprising cross-linked molecules of a polyhydroxylic polymer comprising hydroxyl groups and having anionic functional groups comprising carboxylic, phosphate, metaphosphate, or sulfonate functional groups, or combinations thereof, said anionic functional groups providing a negative charge to said microparticles, and interacting ionically with said positively charged drug; said cross-linked molecules of a polyhydroxylic polymer having a degree of substitution of hydroxyl groups of about 0.1 to about 0.9, and an exchange capacity of from about 0.1 to 2.76 mEq of said anionic functional groups per mL of said cross-linked molecules of a polyhydroxylic polymer, said plurality of microparticles being operable to provide a size distribution of about 45 pm to 1200 pm, and a pharmaceutically acceptable excipient.

[0012] The polyhydroxylic polymer may be a polyvinyl alcohol (PVA) a native starch (S), or a carboxymethylstarch (CMS), or a combination thereof.

[0013] The polyhydroxylic polymer may be PVA having a molecular weight of about 13 kDa to about 130 kDa.

[0014] The microparticles may be spherical microparticles, non-spherical microparticles or a combination thereof.

[0015] The CMS may have a molecular weight of about 50 to about 150 Da, with preference of about 100 kDa to about 150 kDa.

[0016] The CMS may have a degree of substitution of about 0.1 to about 0.3.

[0017] The cross-linked molecules of a polyhydroxylic polymer may have a cross-linking degree of about 1 % to about 50 %, with preference for about 1% to about 10%.

[0018] The anionic functional groups may comprise a metaphosphate group.

[0019] The polyhydroxylic polymer may be cross-linked with sodium trimetaphosphate (STMP), sodium hexametaphosphate (SHMP), or a combination thereof.

[0020] The anionic functional groups may further comprise 1) anionic functional groups providing a cross-link between the cross-linked molecules of a polyhydroxylic polymer, or 2) anionic functional groups providing a negative charge to the microparticles for interacting ionically with the positively charged drug and a cross-link between the cross-linked molecules of a polyhydroxylic polymer.

[0021] In the pharmaceutical composition of the present invention, where the polyhydroxylic polymer is a polyvinyl alcohol (PVA), a native starch (S) or a combination thereof, and the anionic functional groups comprise a metaphosphate group, the metaphosphate group may comprise 1) first metaphosphate groups providing a negative charge to the microparticles for interacting ionically with the positively charged drug; 2) second metaphosphate groups providing a cross-link between the cross-linked molecules of a polyhydroxylic polymer; and 3) third metaphosphate groups providing a negative charge to the microparticles for interacting ionically with the positively charged drug and providing a cross-link between the cross-linked molecules of a polyhydroxylic polymer.

[0022] In the pharmaceutical composition of the present invention, where the polyhydroxylic polymer is a carboxymethylstarch (CMS), and the anionic functional groups comprise a carboxyl group and a metaphosphate group, and the metaphosphate group may comprise 1) first metaphosphate groups providing a negative charge to the microparticles for interacting ionically with the positively charged drug; 2) second metaphosphate groups providing a cross-link between the cross-linked molecules of a polyhydroxylic polymer; and 3) third metaphosphate groups providing a negative charge to the microparticles for interacting ionically with the positively charged drug and providing a cross-link between the cross-linked molecules of a polyhydroxylic polymer.

[0023] The polyhydroxylic polymer may be a polyvinyl alcohol (PVA), a starch (S) or a combination thereof, and the anionic functional groups comprise a metaphosphate (MP) group. The metaphosphate group is coming from the cross-linker STMP that generated a cross-link between the molecules of a polyhydroxylic polymer and, with this, also provided the anionic MP group (Figure 2).

[0024] The polyhydroxylic polymer may be a carboxymethylstarch (CMS) cross-linked with STMP, and the anionic functional groups comprise a carboxyl group and a metaphosphate group

[0025] The plurality of microparticles may be operable to provide size distribution of about 100 pm to 900 pm.

[0026] The plurality of microparticles may be operable to provide a preferred size distribution of about 300 pm to 900 pm.

[0027] The plurality of microparticles may be enabled to provide a size distribution of about 500 pm to 800 pm.

[0028] The positively charged drug may be an anesthetic agent, a chemotherapeutic agent, a narcotic, a nonsteroidal anti-inflammatory drug, an antibiotic, or combinations thereof.

[0029] The anesthetic agent may be lidocaine, bupivacaine, ropivacaine, or a combination thereof.

[0030] The anesthetic agent may be lidocaine.

[0031] The polyhydroxylic polymer may be PVA, CMS, CLS ora combination thereof, and may have a drug loading capacity of about 3600 mg of lidocaine per gram of cross-linked molecules of a polyhydroxylic polymer.

[0032] The chemotherapeutic agent may be adriamycine, irinotecan, epirubicine, or combinations thereof.

[0033] The nonsteroidal anti-inflammatory drug may be ketorolac.

[0034] The narcotic may be tramadol, oxycodone, or combinations thereof.

[0035] The antibiotic may be ciprofloxacin, tetracycline, clindamycine, or combinations thereof.

[0036] The angiogenesis inhibitor may be bevacizumab.

[0037] The plurality of microparticles may have loaded thereon from about 0.1 to about 560 mg of the positively charged drug per mL of microparticles.

[0038] The pharmaceutical composition may be for use in vascular embolization, radioembolization, or both in a patient in need thereof.

[0039] The pharmaceutical composition may be for use in the management of pain during or after vascular embolization, radio-embolization, or both in a patient in need thereof.

[0040] A method for vascular embolization, radio-embolization, or both, of a blood vessel in a patient in need thereof comprising administering to the patient of the pharmaceutical composition of the present invention.

[0041] According to another embodiment, there is provided a method for the management of pain during and after vascular embolization, radio-embolization, or both, of a blood vessel in a patient in need thereof comprising administering to the patient the pharmaceutical composition of the present invention.

[0042] The vascular embolization may be vascular embolization of uterine arteries.

[0043] The vascular embolization of uterine arteries may be for the treatment of uterine fibroids.

[0044] The cross-linked molecules of a polyhydroxylic polymer may be a polyvinyl alcohol cross-linked polymer having from about 0.1 to about 1.0 mEq of the anionic functional groups per gram of the cross-linked molecules of a polyhydroxylic polymer on a dry basis, preferably 0.33 mEq / mL.

[0045] The cross-linked molecules of a polyhydroxylic polymer may be a carboxymethylstarch cross-linked polymer having from about 0.1 to about 2.76 mEq of the anionic functional groups per mL of the cross-linked molecules of a polyhydroxylic polymer, preferably 0.27 mEq / mL.

[0046] The following terms are defined below.

[0047] The term “polyvinyl alcohol” (PVA) is intended to refer to the water-soluble synthetic polymer having generic formula:

[0048] Polyvinyl alcohol is used in a variety of medical applications because of its biocompatibility, low tendency for protein adhesion, and low toxicity. In the context of the present invention, PVA may have a molecular weight range of from about 13000 to 130000 Da (13 to 130 kDa).

[0049] The term of starch includes both starch components: amylose and amylopectin, irrespective of their ratio. As used herein, the terms “starch” or “native starch” on their own, refers to native starch refers to the naturally occurring, unmodified form of starch extracted from plants like corn, wheat, potatoes, or rice, without undergoing any chemical or physical modifications.

[0050] The term “carboxymethylstarch” (CMS) is intended to refer to an etherified anionic starch derivative, a modified starch in which the hydroxyl groups on some of the glucose units are derivatized by carboxymethyl groups. CMS is a water-soluble polysaccharide which is widely employed as an additive; it is a biodegradable and non-toxic product. In the context of the present invention, it may have (but not limited to) a molecular weight range of from about 100000 to 150000 Da, and a degree of substitution of about 0.10 to about 1.50, preferably 0.15 to 0.30 in a conventional system with maximal substitution is 3 (corresponding to 3 hydroxyl groups / glucose unit, susceptible for substitution),

[0051] Carboxymethyl-starch (CMS) is obtained in various forms by grafting of anionic groups (carboxy methyl [CM]) on starch by treatment with monochloroacetic acid. This functionalization isusually performed in organic phase to obtain higher yields and elevated degrees of substitution (DS). A commercial product: the Sodium starch glycolate is a carboxymethyl potato starch with superdisintegrant properties.

[0052] This invention may also use a recently described CMS obtained in aqueous phase - a procedure that may lead to a better acceptability by the regulatory organizations (Labelle et al, 2023). The approach of starch carboxymethylation in aqueous phase, allows to obtain a product with selfassembling properties rather than fast hydratability. In addition of Carboxymethylation, a cross-linking with STMP is proposed, to obtain CMS-CL with the aim to enhance stability and anionic character of CMS-CL ant thus its drug loading capacity.

[0053] Also a starch crosslinked with STMP is proposed hereto, referred to as CLS-MP, presenting metaphosphate (MP) groups.

[0054] The term “polyhydroxylic polymer”, as used herein is intended to mean a polymer which comprises a plurality of hydroxyl groups in the molecule. In embodiments of the present invention, the polyhydroxylic polymer are intended to be a PVA polymer, a native starch, a starch polymer comprising CMS, or cross-linked starch or a combination thereof.

[0055] The terms “cross-linking” or “cross-linked”, as used herein are intended to mean the formation of covalent bonds which hold portions of several polyhydroxylic polymer chains together. As used herein in the context of the present invention, the term means the reaction that occurs through the hydroxyl groups of the polysaccharide or the alcohol of the polymers and that leads, for example, to ester (if cross-linker is STMP) or ether (if cross-linker is, epichlorohydrin) linkages. In reaction with CMS, the cross-linking does not occur through reaction with carboxylic groups, which are free for further modifications.

[0056] The term “anionic functional group” is intended to mean functional groups such as carboxylic, phosphate, metaphosphate, or sulfonate functional groups, or combinations thereof. In embodiments, about 0.033 to about 2.76 mEq of the anionic functional group are present per mL of the cross-linked molecules of a polyhydroxylic polymer.

[0057] The terms “carboxylic” or “carboxylic acid” are intended to mean an organic acid that contains a carboxyl group (-C(=O)-OH) as a substituent functional group of the polyhydroxylic polymer.

[0058] The terms “phosphate” or “orthophosphate” are intended to mean the functional group - [PO4]3" as a substituent functional group of the polyhydroxylic polymer.

[0059] The term “metaphosphate” is intended to mean the -PO3_as a substituent functional group of the polyhydroxylic polymer.

[0060] The terms “sulfonate” are intended to mean functional group -S(=O)2-O" as a substituent functional group of the polyhydroxylic polymer.

[0061] The term “microparticle” means a polymeric granule or combinations of polymeric granules made into micron size particles of various sizes. The microparticles may have a variety of shapes.

[0062] The terms “particle-size distribution” or “size distribution” are intended to mean the range of the values of sizes of particles, particularly of the microparticles found in the present invention.

[0063] The particle-size distribution is for swollen particles or for particles that do not swell in use, i.e., the particles have a particle-size distribution before use and they maintain this particle-size distribution in use.

[0064] The expression “operable to provide”, in the context of the particle-size distribution (or the size distribution) is intended to mean that the particles, when in use for their intended purpose, have the indicated size distribution. According to an embodiment, the expression “operable to provide a size distribution” is intended to refer to the final size distribution of the particles as they are being used for their intended purpose. According to an embodiment, this may mean that the particles of the present invention, when they are reconstituted, will have the indicated size distribution. According to an embodiment, this may mean that the particles of the present invention may not need to be reconstituted, and that they have the indicated size distribution.

[0065] The terms “reconstituted” or “reconstitution” are intended to mean the addition of the dry microparticles of the present invention to a liquid such as to obtain the reconstituted swollen microparticles. In embodiments, the fluids are pharmaceutically acceptable media, preferably physiologically acceptable solutions comprising water. Through the process of reconstitution, the dry microparticles absorb the liquid or fluid and their volume increases. For example, reconstitution of starch-based microparticles according to the present invention may result in the volume of the microparticles increasing up to10-fold.

[0066] The term “dry basis” is intended to refer to a substance, here the cross-linked polyhydroxylic polymer, in solid state, and / or prior to addition of fluids or liquids to the substance before reconstitution.

[0067] The term “composition” as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly orindirectly, from combination of the specified ingredients in the specified amounts. Such term in relation to a pharmaceutical composition or other compositions in general, is intended to encompass a product comprising the active ingredient(s) and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions or other compositions in general of the present invention encompass any composition made by admixing microparticles of the present invention and a pharmaceutically acceptable carrier. By “pharmaceutically acceptable” or “acceptable” it is meant the carrier, diluent, or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0068] The term “uterine fibroids”, as used herein is intended to refer to the condition caused by the presence of benign uterine tumors containing fibrous tissue.

[0069] The term “vascular embolization”, as used herein is intended to mean a procedure used to stop the blood flow to a certain part of a body or organ by blocking a small artery or vein.

[0070] The term “excipient”, as used herein is intended to encompass any and all, dispersion media, diluents, or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington's The Science and Practice of Pharmacy, 21stEdition, A. R. Gennaro (Lippincott, Williams & Wilkins, Baltimore, MD., 2006) discloses various excipients used in formulating pharmaceutical compositions and known techniques for the preparation thereof. Except insofar as any conventional excipient medium is incompatible with a substance or its derivatives, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated to be within the scope of this invention. Pharmaceutically acceptable excipients used in the manufacture of pharmaceutical compositions include, but are not limited to, inert diluents, dispersing and / or granulating agents, surface active agents and / or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and / or oils. Such excipients may optionally be included in pharmaceutical compositions.

[0071] The term “ionic interactions”, as used herein is intended to refer to the reaction formed by electrostatic attraction between two groups of opposite charge.

[0072] The term “drug”, as used herein, is intended to mean any substance, compound, active pharmaceutical ingredient that is used to prevent, treat, or relieve symptoms of a disease or abnormal condition.

[0073] The term “positively charged”, as used herein, is intended to refer to drugs, and particularly drugs that have a net positive electric charge.

[0074] The term “drug loading capacity”, as used herein is intended to mean the amount of drug (in unit weight) loaded per unit volume (e.g., mL) of reconstituted microparticle of cross-linked polyhydroxylic polymer. Microparticles of the present invention are used in a reconstituted state, after addition of the fluid pharmaceutical excipient and loaded with the desired drug.

[0075] The term “exchange capacity”, as used herein, is intended to mean the amount of ions that can be exchanged / stored per unit of mass of the polyhydroxylic polymer. Typically it is expressed in milliequivalents of ion per gram of polyhydroxylic polymer (mEq / g).

[0076] As used herein, the term “about” is used to indicate some degree of variation, e.g., ±10% or ±5%, around the given value.

[0077] The term “subject” as used herein, is a human patient or animal such as another mammal.

[0078] Before describing the present invention in detail, a number of terms will be defined. As used herein, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise.

[0079] It is noted that terms like “preferably”, “commonly”, and “typically” are not utilized herein to limit the scope of the claimed invention or to imply that certain features are critical, essential, or even important to the structure or function of the claimed invention. Rather, these terms are merely intended to highlight alternative or additional features that can or cannot be utilized in a particular embodiment of the present invention.

[0080] For the purposes of describing and defining the present invention it is noted that the term “substantially” is utilized herein to represent the inherent degree of uncertainty that can be attributed to any quantitative comparison, value, measurement, or other representation. The term “substantially” is also utilized herein to represent the degree by which a quantitative representation can vary from a stated reference without resulting in a change in the basic function of the subject matter at issue.

[0081] Features and advantages of the subject matter hereof will become more apparent in light of the following detailed description of selected embodiments, as illustrated in the accompanying figures. As will be realized, the subject matter disclosed and claimed is capable of modifications in various respects, all without departing from the scope of the claims. Accordingly, the drawings and thedescription are to be regarded as illustrative in nature, and not as restrictive and the full scope of the subject matter is set forth in the claims.BRIEF DESCRIPTION OF THE DRAWINGS

[0082] Further features and advantages of the present disclosure will become apparent from the following detailed description, taken in combination with the appended drawings, in which:

[0083] Fig. 1 illustrates schematically the uterine fibroid embolization.

[0084] Fig. 2 illustrates the PVA cross-linking with STMP to generate a cross-linked polyvinyl alcohol with metaphosphate groups (CLPVA-MP).

[0085] Fig. 3 illustrates the ionic binding of cationic lidocaine to the anionic metaphosphate groups of the CLPVA-MP.

[0086] Fig. 4 illustrates the influence of lidocaine concentration at loading of CLPVA-MP10, of CLS-MP5 and of CLS-MP10. Maximal loading capacity (saturation) was considered when no more increase of retained lidocaine was found at increasing amounts of lidocaine.

[0087] Fig. 5 illustrates the time-course of lidocaine loading on polyhydroxylic materials exhibiting anionic MP groups.

[0088] Fig. 6 illustrates the lidocaine release pattern from polyhydroxylic materials with MP groups and from DC beads with sulfonate groups.

[0089] Fig. 7 illustrates the loading profile of (A) Lidocaine and (B) Bupivacaine, on CLPVA- MP10, on CLS-MP5 and on CLS-MP10 microparticles. The concentration (7.5 mg / mL) was that used for bupivacaine (Marcaine ®) and lidocaine was loading at same concentration in order to compare the two analgesics.

[0090] Fig. 8A illustrates micrographs of CLPVA-MP10 microparticles swollen in NaCI 0.9% w / v.

[0091] Fig. 8B illustrates micrographs of CLS-MP5 microparticles swollen in NaCI 0.9% w / v.

[0092] Fig. 8C illustrates micrographs of CLS-MP10 microparticles swollen in NaCI 0.9% w / v.

[0093] Fig. 9A illustrates CLPVA-MP microparticles unloaded with lidocaine after passage through a microcatheter.

[0094] Fig. 9B illustrates CLPVA-MP microparticles loaded with lidocaine after passage through a microcatheter.DETAILED DESCRIPTION

[0095] The present invention is directed to a pharmaceutical composition comprising a plurality of microparticles loaded with a positively charged drug, and a pharmaceutically acceptable excipient.

[0096] The composition comprises a plurality of microparticles comprising cross-linked molecules of a polyhydroxylic polymer. These polyhydroxylic polymers are substituted with anionic functional groups, such as carboxylic functional groups, phosphate functional groups, metaphosphate functional groups, or sulfonate functional groups, or combinations thereof. The anionic functional groups provide a negative charge to the microparticles, interacting ionically with the positively charged drug.

[0097] According to embodiments of the present invention, the polyhydroxylic polymer may have a degree of substitution of hydroxyl groups of about 0.1 to about 1 .5.

[0098] According to embodiments of the present invention, the polyhydroxylic polymer may have an exchange capacity of about 0.1 to about 2.76 mEq of the anionic functional group present per mL of the cross-linked molecules of a polyhydroxylic polymer.

[0099] The microparticles have a high drug loading capacity. The plurality of microparticles having loaded thereon from about 0.1 to about 560 mg of the positively charged drug per mL of microparticles.

[0100] The plurality of microparticles being operable to provide a size distribution of about 45 pm to 1200 pm.Shape and size of particles

[0101] According to another embodiment, the microparticles may be spherical, non-spherical, or a combination thereof.

[0102] According to embodiments, the plurality of microparticles are operable to provide a size distribution of from about 45 pm to about 1200 pm, from about 50 pm to about 1200 pm, or from about 100 pm to about 1200 pm, or from about 150 pm to about 1200 pm, or from about 200 pm to about 1200 pm, or from about 250 pm to about 1200 pm, or from about 300 pm to about 1200 pm, or from about 350 pm to about 1200 pm, or from about 400 pm to about 1200 pm, or from about 450 pm to about 1200 pm, or from about 500 pm to about 1200 pm, or from about 550 pm to about 1200 pm, or from about 600 pm to about 1200 pm, or from about 650 pm to about 1200 pm, or from about 700 pm to about 1200 pm, or from about 750 pm to about 1200 pm, or from about 800 pm to about 1200 pm, or from about 850 pm to about 1200 pm, or from about 900 pm to about 1200 pm, or from about 950 pm to about 1200 pm, or from about 1000 pm to about 1200 pm, or from about 1050 pm to about 1200pm, or from about 1100 pm to about 1200 pm, or from about 1150 pm to about 1200 pm, or from about 45 pm to about 1150 pm, or from about 50 pm to about 1150 pm, or from about 100 pm to about 1150 pm, or from about 150 pm to about 1150 pm, or from about 200 pm to about 1150 pm, or from about 250 pm to about 1150 pm, or from about 300 pm to about 1150 pm, or from about 350 pm to about 1150 pm, or from about 400 pm to about 1150 pm, or from about 450 pm to about 1150 pm, or from about 500 pm to about 1150 pm, or from about 550 pm to about 1150 pm, or from about 600 pm to about 1150 pm, or from about 650 pm to about 1150 pm, or from about 700 pm to about 1150 pm, or from about 750 pm to about 1150 pm, or from about 800 pm to about 1150 pm, or from about 850 pm to about 1150 pm, or from about 900 pm to about 1150 pm, or from about 950 pm to about 1150 pm, or from about 1000 pm to about 1150 pm, or from about 1050 pm to about 1150 pm, or from about 1100 pm to about 1150 pm, or from about 45 pm to about 1100 pm, or from about 50 pm 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about 250 pm to about 1050 pm, or from about 300 pm to about 1050 pm, or from about 350 pm to about 1050 pm, or from about 400 pm to about 1050 pm, or from about 450 pm to about 1050 pm, or from about 500 pm to about 1050 pm, or from about 550 pm to about 1050 pm, or from about 600 pm to about 1050 pm, or from about 650 pm to about 1050 pm, or from about 700 pm to about 1050 pm, or from about 750 pm to about 1050 pm, or from about 800 pm to about 1050 pm, or from about 850 pm to about 1050 pm, or from about 900 pm to about 1050 pm, or from about 950 pm to about 1050 pm, or from about 1000 pm to about 1050 pm, or from about 45 pm to about 1000 pm, or from about 50 pm to about 1000 pm, or from about 100 pm to about 1000 pm, or from about 150 pm to about 1000 pm, or from about 200 pm to about 1000 pm, or from about 250 pm to about 1000 pm, or from about 300 pm to about 1000 pm, or from about 350 pm to about 1000 pm, or from about 400 pm to about 1000 pm, or from about 450 pm to about 1000 pm, or from about 500 pm to about 1000 pm, or from about 550 pm to about 1000 pm, or from about 600 pm to about 1000 pm, or from about 650 pm to about 1000 pm, or from about 700 pm to about 1000 pm, or from about 750 pm to about 1000 pm, or from about 800 pm to about 1000 pm, or from about 850 pm to about1000 pm, or from about 900 pm to about 1000 pm, or from about 950 pm to about 1000 pm, or from about 45 pm to about 950 pm, or from about 50 pm to about 950 pm, or from about 100 pm to about 950 pm, or from about 150 pm to about 950 pm, or from about 200 pm to about 950 pm, or from about 250 pm to about 950 pm, or from about 300 pm to about 950 pm, or from about 350 pm to about 950 pm, or from about 400 pm to about 950 pm, or from about 450 pm to about 950 pm, or from about 500 pm to about 950 pm, or from about 550 pm to about 950 pm, or from about 600 pm to about 950 pm, or from about 650 pm to about 950 pm, or from about 700 pm to about 950 pm, or from about 750 pm to about 950 pm, or from about 800 pm to about 950 pm, or from about 850 pm to about 950 pm, or from about 900 pm to about 950 pm, or from about 45 pm to about 900 pm, or from about 50 pm to about 900 pm, or from about 100 pm to about 900 pm, or from about 150 pm to about 900 pm, or from about 200 pm to about 900 pm, or from about 250 pm to about 900 pm, or from about 300 pm to about 900 pm, or from about 350 pm to about 900 pm, or from about 400 pm to about 900 pm, or from about 450 pm to about 900 pm, or from about 500 pm to about 900 pm, or from about 550 pm to about 900 pm, or from about 600 pm to about 900 pm, or from about 650 pm to about 900 pm, or from about 700 pm to about 900 pm, or from about 750 pm to about 900 pm, or from about 800 pm to about 900 pm, or from about 850 pm to about 900 pm, or from about 45 pm to about 850 pm, or from about 50 pm to about 850 pm, or from about 100 pm to about 850 pm, or from about 150 pm to about 850 pm, or from about 200 pm to about 850 pm, or from about 250 pm to about 850 pm, or from about 300 pm to about 850 pm, or from about 350 pm to about 850 pm, or from about 400 pm to about 850 pm, or from about 450 pm to about 850 pm, or from about 500 pm to about 850 pm, or from about 550 pm to about 850 pm, or from about 600 pm to about 850 pm, or from about 650 pm to about 850 pm, or from about 700 pm to about 850 pm, or from about 750 pm to about 850 pm, or from about 800 pm to about 850 pm, or from about 45 pm to about 800 pm, or from about 50 pm to about 800 pm, or from about 100 pm to about 800 pm, or from about 150 pm to about 800 pm, or from about 200 pm to about 800 pm, or from about 250 pm to about 800 pm, or from about 300 pm to about 800 pm, or from about 350 pm to about 800 pm, or from about 400 pm to about 800 pm, or from about 450 pm to about 800 pm, or from about 500 pm to about 800 pm, or from about 550 pm to about 800 pm, or from about 600 pm to about 800 pm, or from about 650 pm to about 800 pm, or from about 700 pm to about 800 pm, or from about 750 pm to about 800 pm, or from about 45 pm to about 750 pm, or from about 50 pm to about 750 pm, or from about 100 pm to about 750 pm, or from about 150 pm to about 750 pm, or from about 200 pm to about 750 pm, or from about 250 pm to about 750 pm, or from about 300 pm to about 750 pm, or from about 350 pm to about 750 pm, or from about 400 pm to about 750 pm, or from about 450 pm to about 750 pm, or from about 500 pm to about 750 pm, or from about 550 pm to about 750 pm, or from about 600 pm to about 750 pm, or from about 650 pm to about 750 pm, or from about 700 pm to about 750 pm, or from about 45 pm to about 700 pm, or from about 50 pm to about 700 pm, or from about 100pm to about 700 pm, or from about 150 pm to about 700 pm, or from about 200 pm to about 700 pm, or from about 250 pm to about 700 pm, or from about 300 pm to about 700 pm, or from about 350 pm to about 700 pm, or from about 400 pm to about 700 pm, or from about 450 pm to about 700 pm, or from about 500 pm to about 700 pm, or from about 550 pm to about 700 pm, or from about 600 pm to about 700 pm, or from about 650 pm to about 700 pm, or from about 45 pm to about 650 pm, or from about 50 pm to about 650 pm, or from about 100 pm to about 650 pm, or from about 150 pm to about 650 pm, or from about 200 pm to about 650 pm, or from about 250 pm to about 650 pm, or from about 300 pm to about 650 pm, or from about 350 pm to about 650 pm, or from about 400 pm to about 650 pm, or from about 450 pm to about 650 pm, or from about 500 pm to about 650 pm, or from about 550 pm to about 650 pm, or from about 600 pm to about 650 pm, or from about 45 pm to about 600 pm, or from about 50 pm to about 600 pm, or from about 100 pm to about 600 pm, or from about 150 pm to about 600 pm, or from about 200 pm to about 600 pm, or from about 250 pm to about 600 pm, or from about 300 pm to about 600 pm, or from about 350 pm to about 600 pm, or from about 400 pm to about 600 pm, or from about 450 pm to about 600 pm, or from about 500 pm to about 600 pm, or from about 550 pm to about 600 pm, or from about 45 pm to about 550 pm, or from about 50 pm to about 550 pm, or from about 100 pm to about 550 pm, or from about 150 pm to about 550 pm, or from about 200 pm to about 550 pm, or from about 250 pm to about 550 pm, or from about 300 pm to about 550 pm, or from about 350 pm to about 550 pm, or from about 400 pm to about 550 pm, or from about 450 pm to about 550 pm, or from about 500 pm to about 550 pm, or from about 45 pm to about 500 pm, or from about 50 pm to about 500 pm, or from about 100 pm to about 500 pm, or from about 150 pm to about 500 pm, or from about 200 pm to about 500 pm, or from about 250 pm to about 500 pm, or from about 300 pm to about 500 pm, or from about 350 pm to about 500 pm, or from about 400 pm to about 500 pm, or from about 450 pm to about 500 pm, or from about 45 pm to about 450 pm, or from about 50 pm to about 450 pm, or from about 100 pm to about 450 pm, or from about 150 pm to about 450 pm, or from about 200 pm to about 450 pm, or from about 250 pm to about 450 pm, or from about 300 pm to about 450 pm, or from about 350 pm to about 450 pm, or from about 400 pm to about 450 pm, or from about 45 pm to about 400 pm, or from about 50 pm to about 400 pm, or from about 100 pm to about 400 pm, or from about 150 pm to about 400 pm, or from about 200 pm to about 400 pm, or from about 250 pm to about 400 pm, or from about 300 pm to about 400 pm, or from about 350 pm to about 400 pm, or from about 45 pm to about 350 pm, or from about 50 pm to about 350 pm, or from about 100 pm to about 350 pm, or from about 150 pm to about 350 pm, or from about 200 pm to about 350 pm, or from about 250 pm to about 350 pm, or from about 300 pm to about 350 pm, or from about 45 pm to about 300 pm, or from about 50 pm to about 300 pm, or from about 100 pm to about 300 pm, or from about 150 pm to about 300 pm, or from about 200 pm to about 300 pm, or from about 250 pm to about 300 pm, or from about 45 pm to about 250 pm, or from about 50 pm to about 250 pm, or fromabout 100 pm to about 250 pm, or from about 150 pm to about 250 pm, or from about 200 pm to about 250 pm, or from about 45 pm to about 200 pm, or from about 50 pm to about 200 pm, or from about 100 pm to about 200 pm, or from about 150 pm to about 200 pm, or from about 45 pm to about 150 pm, or from about 50 pm to about 150 pm, or from about 100 pm to about 150 pm, or from about 45 pm to about 100 pm, or from about 50 pm to about 100 pm, or from about 45 pm to about 50 pm, or 50 pm, 100 pm, 150 pm, 200 pm, 250 pm, 300 pm, 350 pm, 400 pm, 450 pm, 500 pm, 550 pm, 600 pm, 650 pm, 700 pm, 750 pm, 800 pm, 850 pm, 900 pm, 950 pm, 1000 pm, 1050 pm, 1100 pm, 1150 pm, or 1200 pm, with preference from about 300 pm to about 800 pm.Polyhydroxylic polymers

[0103] The polyhydroxylic polymer may be a polyvinyl alcohol (PVA) polymer, a native starch (S) polymer, or a carboxymethylstarch (CMS) polymer, or a combination thereof.

[0104] According to another embodiment, the polyhydroxylic polymer may be PVA having a molecular weight of about 10 to about 130 kDa, or about 13 to about 130 kDa,or about 20 to about 130 kDa, or about 30 to about 130 kDa, or about 40 to about 130 kDa, or about 50 to about 130 kDa, or about 60 to about 130 kDa, or about 70 to about 130 kDa, or about 80 to about 130 kDa, or about 90 to about 130 kDa, or about 100 to about 130 kDa, or about 110 to about 130 kDa, or about 120 to about 130 kDa, or about 10 to about 120 kDa, or about 20 to about 120 kDa, or about 30 to about 120 kDa, or about 40 to about 120 kDa, or about 50 to about 120 kDa, or about 60 to about 120 kDa, or about 70 to about 120 kDa, or about 80 to about 120 kDa, or about 90 to about 120 kDa, or about 100 to about 120 kDa, or about 110 to about 120 kDa, or about 10 to about 110 kDa, or about 20 to about 110 kDa, or about 30 to about 110 kDa, or about 40 to about 110 kDa, or about 50 to about 110 kDa, or about 60 to about 110 kDa, or about 70 to about 110 kDa, or about 80 to about 110 kDa, or about 90 to about 110 kDa, or about 100 to about 110 kDa, or about 10 to about 100 kDa, or about 20 to about 100 kDa, or about 30 to about 100 kDa, or about 40 to about 100 kDa, or about 50 to about 100 kDa, or about 60 to about 100 kDa, or about 70 to about 100 kDa, or about 80 to about 100 kDa, or about 90 to about 100 kDa, or about 10 to about 90 kDa, or about 20 to about 90 kDa, or about 30 to about 90 kDa, or about 40 to about 90 kDa, or about 50 to about 90 kDa, or about 60 to about 90 kDa, or about 70 to about 90 kDa, or about 80 to about 90 kDa, or about 10 to about 80 kDa, or about 20 to about 80 kDa, or about 30 to about 80 kDa, or about 40 to about 80 kDa, or about 50 to about 80 kDa, or about 60 to about 80 kDa, or about 70 to about 80 kDa, or about 10 to about 70 kDa, or about 20 to about 70 kDa, or about 30 to about 70 kDa, or about 40 to about 70 kDa, or about 50 to about 70 kDa, or about 60 to about 70 kDa, or about 10 to about 60 kDa, or about 20 to about 60 kDa, or about 30 to about 60 kDa, or about 40 to about 60 kDa, or about 50 to about 60 kDa, or about 10 to about 50 kDa, or about 20 to about 50 kDa, or about 30 to about 50 kDa, or about 40 to about 50 kDa, or about 10 toabout 40 kDa, or about 20 to about 40 kDa, or about 30 to about 40 kDa, or about 10 to about 30 kDa, or about 20 to about 30 kDa, or about 10 to about 20 kDa, or about 10, 13, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, or 130 kDa, and preferably from about 100 kDa to about 130 kDa.

[0105] According to another embodiment, the polyhydroxylic polymer may be a native starch and / or a CMS having a molecular weight of about 100 to about 150 kDa, or of about 110 to about 150 kDa, or of about 120 to about 150 kDa, or of about 130 to about 150 kDa, or of about 140 to about 150 kDa, of about 100 to about 140 kDa, or of about 110 to about 140 kDa, or of about 120 to about 140 kDa, or of about 130 to about 140 kDa, or of about 100 to about 130 kDa, or of about 110 to about 130 kDa, or of about 120 to about 130 kDa, or of about 100 to about 120 kDa, or of about 110 to about 120 kDa, or of about 100 to about 110 kDa, or 100, 110, 120, 130, 140, 150 kDa.

[0106] Although modified by cross-linking with STMP or by carboxymethylation, the CLS-MP and the CMS are still substrates for alpha-amylase, an enzyme that is secreted by the salivary glands, including the parotid gland, in large amount for oral cavity but also in very small quantities into the bloodstream. CLS or CMS are subject to the slow degradation by alpha-amylase and, hereby, allows for modulation of liberation of the therapeutic agent. This susceptibility to slow amylolysis is a great advantage because: 1) controls analgesic release for 24 h or more and, 2) low amylolysis provides slow elimination of CMS-type microspheres. Consequently, and advantageously, patient’s peak serum concentration of the positively charged drug decreases relative to the patient.

[0107] Serum concentration of alpha-amylase is low enough (except cases of pancreatitis or parotiditis). The low level of alpha-amylase may control the release of the positively charged drug administered by intra-arterial injection and also to induce a slow hydrolysis of the CMS microparticles gradually reestablishing the circulation in several days (weeks). This behavior prevents a rapid increase in serum drug concentration that can lead to systemic toxicity. In addition, this allows for the positively charged drug to have a longer effect. Also, late ischemic pain (beyond the time required for fibroid necrosis) could be reduced by the resolution of the vascular blockage with the resorption of the embolic material.Degree of substitution of the polyhydroxylic polymer

[0108] The degree of substitution (DS) of a polyhydroxylic polymer is defined as the number of substituted hydroxyl groups on each monomer unit of the polymer, where the maximal theoretical value, DS = 3.

[0109] According to an embodiment, the polyhydroxylic polymer may have a degree of substitution of hydroxyl groups of from about 0.1 to about 1 .5, or from about 0.2 to about 1 .5, or from about 0.3 to about 1 .5, or from about 0.4 to about 1 .5, or from about 0.5 to about 1 .5, or from about0.6 to about 1 .5, or from about 0.7 to about 1 .5, or from about 0.8 to about 1 .5, or from about 0.9 to about 1.5, or from about 1 to about 1.5, or from about 1.1 to about 1.5, or from about 1.2 to about 1.5, or from about 1 .3 to about 1 .5, or from about 1 .4 to about 1 .5, or from about 0.1 to about 1 .4, or from about 0.2 to about 1 .4, or from about 0.3 to about 1 .4, or from about 0.4 to about 1 .4, or from about 0.5 to about 1 .4, or from about 0.6 to about 1 .4, or from about 0.7 to about 1 .4, or from about 0.8 to about 1.4, or from about 0.9 to about 1.4, or from about 1 to about 1.4, or from about 1.1 to about 1.4, or from about 1 .2 to about 1 .4, or from about 1 .3 to about 1 .4, or from about 0.1 to about 1 .3, or from about 0.2 to about 1 .3, or from about 0.3 to about 1 .3, or from about 0.4 to about 1 .3, or from about 0.5 to about 1 .3, or from about 0.6 to about 1 .3, or from about 0.7 to about 1 .3, or from about 0.8 to about 1.3, or from about 0.9 to about 1.3, or from about 1 to about 1.3, or from about 1.1 to about 1.3, or from about 1 .2 to about 1 .3, or from about 0.1 to about 1 .2, or from about 0.2 to about 1 .2, or from about 0.3 to about 1 .2, or from about 0.4 to about 1 .2, or from about 0.5 to about 1 .2, or from about0.6 to about 1 .2, or from about 0.7 to about 1 .2, or from about 0.8 to about 1 .2, or from about 0.9 to about 1.2, or from about 1 to about 1 .2, or from about 1 .1 to about 1.2, or from about 0.1 to about 1.1 , or from about 0.2 to about 1.1 , or from about 0.3 to about 1.1 , or from about 0.4 to about 1.1 , or from about 0.5 to about 1.1 , or from about 0.6 to about 1.1 , or from about 0.7 to about 1.1 , or from about0.8 to about 1.1 , or from about 0.9 to about 1.1 , or from about 1 to about 1.1 , or from about 0.1 to about 1 .0, or from about 0.2 to about 1 .0, or from about 0.3 to about 1 .0, or from about 0.4 to about 1 .0, or from about 0.5 to about 1.0, or from about 0.6 to about 1.0, or from about 0.7 to about 1.0, or from about 0.8 to about 1 .0, or from about 0.9 to about 1 .0, or from about 0.1 to about 0.9, or from about 0.2 to about 0.9, or from about 0.3 to about 0.9, or from about 0.4 to about 0.9, or from about 0.5 to about 0.9, or from about 0.6 to about 0.9, or from about 0.7 to about 0.9, or from about 0.8 to about 0.9, or from about 0.1 to about 0.8, or from about 0.2 to about 0.8, or from about 0.3 to about 0.8, or from about 0.4 to about 0.8, or from about 0.5 to about 0.8, or from about 0.6 to about 0.8, or from about 0.7 to about 0.8, or from about 0.1 to about 0.7, or from about 0.2 to about 0.7, or from about 0.3 to about 0.7, or from about 0.4 to about 0.7, or from about 0.5 to about 0.7, or from about 0.6 to about 0.7, or from about 0.1 to about 0.6, or from about 0.2 to about 0.6, or from about 0.3 to about 0.6, or from about 0.4 to about 0.6, or from about 0.5 to about 0.6, or from about 0.1 to about 0.5, or from about 0.2 to about 0.5, or from about 0.3 to about 0.5, or from about 0.4 to about 0.5, or from about 0.1 to about 0.4, or from about 0.2 to about 0.4, or from about 0.3 to about 0.4, or from about 0.1 to about 0.3, orfrom about 0.2 to about 0.3, orfrom about 0.1 to about 0.1 , from about 0.1 to about 0.5, or from about 0.15 to about 0.5, or from about 0.2 to about 0.5, or from about 0.25 to about 0.5, or from about 0.3 to about 0.5, or from about 0.35 to about 0.5, or from about 0.4 to about 0.5, or from about 0.45 to about 0.5, or from about 0.1 to about 0.45, or from about 0.15 to about 0.45, or from about 0.2 to about 0.45, or from about 0.25 to about 0.45, or from about 0.3 to about 0.45, or fromabout 0.35 to about 0.45, orfrom about 0.4 to about 0.45, orfrom about 0.1 to about 0.4, orfrom about 0.15 to about 0.4, or from about 0.2 to about 0.4, or from about 0.25 to about 0.4, or from about 0.3 to about 0.4, orfrom about 0.35 to about 0.4, or from about 0.1 to about 0.35, or from about 0.15 to about 0.35, orfrom about 0.2 to about 0.35, orfrom about 0.25 to about 0.35, orfrom about 0.3 to about 0.35, or from about 0.1 to about 0.3, orfrom about 0.15 to about 0.3, or from about 0.2 to about 0.3, or from about 0.25 to about 0.3, or from about 0.1 to about 0.25, or from about 0.15 to about 0.25, or from about 0.2 to about 0.25, or from about 0.1 to about 0.2, or from about 0.15 to about 0.2, or from about 0.10 to about 0.15, or about O.1 , 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55. 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1.0, 1.05, 1.1. 1.15, 1.2, 1.25, 1.3, 1.35, 1.4, 1.45, or 1.5 with preference from about 0.15 to about 0.30.Cross-linking degree of the polyhydroxylic polymer

[0110] The cross-linking degree (CLD) is defined as the amount of cross-linking agent (e.g., STMP) used to cross-link 100 g of polyhydroxylic polymer, and may be expression in percent (%). For example, 1 g cross-linking agent used to cross-link 100 g of polyhydroxylic polymer provides a CLD of 1%. According to embodiments, for example Cross-Linked starch: CLS-MP5 and CLS-MP10 may be obtained by starch treatment with STMP at 5 g STMP / 100 g starch or at 10 g STMP / 100 g starch.

[0111] According to an embodiment, the polyhydroxylic polymer may have a degree of crosslinking (or cross-linking degree - CLD) of from about 1 % to about 50%, or from about 10% to about 50%, or from about 20% to about 50%, or from about 30% to about 50%, or from about 40% to about 50%, or from about 1% to about 10%, or about 2% to about 10%, or about 3% to about 10%, or about 4% to about 10%, or about 5% to about 10%, or about 6% to about 10%, or about 7% to about 10%, or about 8% to about 10%, or about 9% to about 10%, or about 1% to about 9%, or about 2% to about 9%, or about 3% to about 9%, or about 4% to about 9%, or about 5% to about 9%, or about 6% to about 9%, or about 7% to about 9%, or about 8% to about 9%, or about 1% to about 8%, or about 2% to about 8%, or about 3% to about 8%, or about 4% to about 8%, or about 5% to about 8%, or about 6% to about 8%, or about 7% to about 8%, or about 1 % to about 7%, or about 2% to about 7%, or about 3% to about 7%, or about 4% to about 7%, or about 5% to about 7%, or about 6% to about 7%, or about 1% to about 6%, or about 2% to about 6%, or about 3% to about 6%, or about 4% to about 6%, or about 5% to about 6%, or about 1 % to about 5%, or about 2% to about 5%, or about 3% to about 5%, or about 4% to about 5%, or about 1 % to about 4%, or about 2% to about 4%, or about 3% to about 4%, or about 1% to about 3%, or about 2% to about 3%, or about 1% to about 2%, or 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10%. According to other embodiments, the CLD may be from about 10% to about 50%, or from about 15% to about 50%, or from about 20% to about 50%, or from about 25% to about 50%,or from about 30% to about 50%, or from about 35% to about 50%, or from about 40% to about 50%, or from about 45% to about 50%, or 10, 15, 20, 25, 30, 35, 40, 45, 50%.Anionic functional groups

[0112] According to embodiments, the anionic functional group may be carboxylic, phosphate, metaphosphate, or sulfonate functional groups, or combinations thereof. Sulfonated polymers are obtained for example by their treatment with 1 ,3-propanesultone. Metaphosphate groups may be obtained by cross-linking of polyhydroxylic polymers with STMP, or sodium hexametaphosphate (SHMP).

[0113] As used herein, “exchange capacity” is intended to mean the amount of ions that can be exchanged / stored per unit of mass of the polyhydroxylic polymer. Typically it is expressed in milliequivalents of ion per mL of polyhydroxylic polymer (mEq / mL). In embodiments, exchange capacities of about 0.1 to about 2.76 mEq of the anionic functional group are present per mL of polyhydroxylic polymer molecules. In embodiments, when the polyhydroxylic polymers are of polyvinyl alcohol cross-linked polymer, they have, exchange capacity of about 0.1 to about 1.0 mEq / mL, and preferably, about 0.33 mEq / mL. In embodiments, when the polymer is a carboxymethyl starch it may have have from about 0.1 to about 2.76 mEq of the anionic functional group per mL, preferably 0.27 mEq / mL.

[0114] Therefore, in embodiments, the cross-linked molecules of a polyhydroxylic polymer may have from about 0.1 to about 0.35 mEq / mL, or from about 0.11 to about 0.35 mEq / mL, or from about 0.12 to about 0.35 mEq / mL, or from about 0.13 to about 0.35 mEq / mL, or from about 0.14 to about 0.35 mEq / mL, or from about 0.15 to about 0.35 mEq / mL, or from about 0.16 to about 0.35 mEq / mL, or from about 0.17 to about 0.35 mEq / mL, or from about 0.18 to about 0.35 mEq / mL, or from about 0.19 to about 0.35 mEq / mL, or from about 0.2 to about 0.35 mEq / mL, or from about 0.21 to about 0.35 mEq / mL, or from about 0.22 to about 0.35 mEq / mL, or from about 0.23 to about 0.35 mEq / mL, or from about 0.24 to about 0.35 mEq / mL, or from about 0.25 to about 0.35 mEq / mL, or from about 0.26 to about 0.35 mEq / mL, or from about 0.27 to about 0.35 mEq / mL, or from about 0.28 to about 0.35 mEq / mL, or from about 0.29 to about 0.35 mEq / mL, or from about 0.3 to about 0.35 mEq / mL, or from about 0.31 to about 0.35 mEq / mL, or from about 0.32 to about 0.35 mEq / mL, or from about 0.33 to about 0.35 mEq / mL, or from about 0.34 to about 0.35 mEq / mL, or from about 0.1 to about 0.34 mEq / mL, or from about 0.11 to about 0.34 mEq / mL, or from about 0.12 to about 0.34 mEq / mL, or from about 0.13 to about 0.34 mEq / mL, or from about 0.14 to about 0.34 mEq / mL, or from about 0.15 to about 0.34 mEq / mL, or from about 0.16 to about 0.34 mEq / mL, or from about 0.17 to about 0.34 mEq / mL, or from about 0.18 to about 0.34 mEq / mL, or from about 0.19 to about 0.34 mEq / mL, or from about 0.2 to about 0.34 mEq / mL, or from about 0.21 to about 0.34 mEq / mL, or fromabout 0.22 to about 0.34 mEq / mL, or from about 0.23 to about 0.34 mEq / mL, or from about 0.24 to about 0.34 mEq / mL, or from about 0.25 to about 0.34 mEq / mL, or from about 0.26 to about 0.34 mEq / mL, or from about 0.27 to about 0.34 mEq / mL, or from about 0.28 to about 0.34 mEq / mL, or from about 0.29 to about 0.34 mEq / mL, or from about 0.3 to about 0.34 mEq / mL, or from about 0.31 to about 0.34 mEq / mL, or from about 0.32 to about 0.34 mEq / mL, or from about 0.33 to about 0.34 mEq / mL, or from about 0.1 to about 0.33 mEq / mL, or from about 0.11 to about 0.33 mEq / mL, or from about 0.12 to about 0.33 mEq / mL, or from about 0.13 to about 0.33 mEq / mL, or from about 0.14 to about 0.33 mEq / mL, or from about 0.15 to about 0.33 mEq / mL, or from about 0.16 to about 0.33 mEq / mL, or from about 0.17 to about 0.33 mEq / mL, or from about 0.18 to about 0.33 mEq / mL, or from about 0.19 to about 0.33 mEq / mL, or from about 0.2 to about 0.33 mEq / mL, or from about 0.21 to about 0.33 mEq / mL, or from about 0.22 to about 0.33 mEq / mL, or from about 0.23 to about 0.33 mEq / mL, or from about 0.24 to about 0.33 mEq / mL, or from about 0.25 to about 0.33 mEq / mL, or from about 0.26 to about 0.33 mEq / mL, or from about 0.27 to about 0.33 mEq / mL, or from about 0.28 to about 0.33 mEq / mL, or from about 0.29 to about 0.33 mEq / mL, or from about 0.3 to about 0.33 mEq / mL, or from about 0.31 to about 0.33 mEq / mL, or from about 0.32 to about 0.33 mEq / mL, or from about 0.1 to about 0.32 mEq / mL, or from about 0.11 to about 0.32 mEq / mL, or from about 0.12 to about 0.32 mEq / mL, or from about 0.13 to about 0.32 mEq / mL, or from about 0.14 to about 0.32 mEq / mL, or from about 0.15 to about 0.32 mEq / mL, or from about 0.16 to about 0.32 mEq / mL, or from about 0.17 to about 0.32 mEq / mL, or from about 0.18 to about 0.32 mEq / mL, or from about 0.19 to about 0.32 mEq / mL, or from about 0.2 to about 0.32 mEq / mL, or from about 0.21 to about 0.32 mEq / mL, or from about 0.22 to about 0.32 mEq / mL, or from about 0.23 to about 0.32 mEq / mL, or from about 0.24 to about 0.32 mEq / mL, or from about 0.25 to about 0.32 mEq / mL, or from about 0.26 to about 0.32 mEq / mL, or from about 0.27 to about 0.32 mEq / mL, or from about 0.28 to about 0.32 mEq / mL, or from about 0.29 to about 0.32 mEq / mL, or from about 0.3 to about 0.32 mEq / mL, or from about 0.31 to about 0.32 mEq / mL, or from about 0.1 to about 0.31 mEq / mL, or from about 0.11 to about 0.31 mEq / mL, or from about 0.12 to about 0.31 mEq / mL, or from about 0.13 to about 0.31 mEq / mL, orfrom about 0.14 to about 0.31 mEq / mL, or from about 0.15 to about 0.31 mEq / mL, orfrom about 0.16 to about 0.31 mEq / mL, or from about 0.17 to about 0.31 mEq / mL, or from about 0.18 to about 0.31 mEq / mL, or from about 0.19 to about 0.31 mEq / mL, or from about 0.2 to about 0.31 mEq / mL, orfrom about 0.21 to about 0.31 mEq / mL, or from about 0.22 to about 0.31 mEq / mL, orfrom about 0.23 to about 0.31 mEq / mL, or from about 0.24 to about 0.31 mEq / mL, or from about 0.25 to about 0.31 mEq / mL, or from about 0.26 to about 0.31 mEq / mL, or from about 0.27 to about 0.31 mEq / mL, orfrom about 0.28 to about 0.31 mEq / mL, or from about 0.29 to about 0.31 mEq / mL, orfrom about 0.3 to about 0.31 mEq / mL, orfrom about 0.1 to about 0.30 mEq / mL, orfrom about 0.11 to about 0.30 mEq / mL, or from about 0.12 to about 0.30 mEq / mL, or from about 0.13 to about 0.30 mEq / mL, orfrom about 0.14 to about 0.30 mEq / mL, or from about 0.15 to about 0.30 mEq / mL, or from about 0.16 to about 0.30 mEq / mL, or from about 0.17 to about 0.30 mEq / mL, or from about 0.18 to about 0.30 mEq / mL, or from about 0.19 to about 0.30 mEq / mL, or from about 0.2 to about 0.30 mEq / mL, or from about 0.21 to about 0.30 mEq / mL, or from about 0.22 to about 0.30 mEq / mL, or from about 0.23 to about 0.30 mEq / mL, or from about 0.24 to about 0.30 mEq / mL, or from about 0.25 to about 0.30 mEq / mL, or from about 0.26 to about 0.30 mEq / mL, or from about 0.27 to about 0.30 mEq / mL, or from about 0.28 to about 0.30 mEq / mL, or from about 0.29 to about 0.30 mEq / mL, or from about 0.1 to about 0.29 mEq / mL, or from about 0.11 to about 0.29 mEq / mL, or from about 0.12 to about 0.29 mEq / mL, or from about 0.13 to about 0.29 mEq / mL, or from about 0.14 to about 0.29 mEq / mL, or from about 0.15 to about 0.29 mEq / mL, or from about 0.16 to about 0.29 mEq / mL, or from about 0.17 to about 0.29 mEq / mL, or from about 0.18 to about 0.29 mEq / mL, or from about 0.19 to about 0.29 mEq / mL, or from about 0.2 to about 0.29 mEq / mL, or from about 0.21 to about 0.29 mEq / mL, or from about 0.22 to about 0.29 mEq / mL, or from about 0.23 to about 0.29 mEq / mL, or from about 0.24 to about 0.29 mEq / mL, or from about 0.25 to about 0.29 mEq / mL, or from about 0.26 to about 0.29 mEq / mL, or from about 0.27 to about 0.29 mEq / mL, or from about 0.28 to about 0.29 mEq / mL, or from about 0.1 to about 0.28 mEq / mL, or from about 0.11 to about 0.28 mEq / mL, or from about 0.12 to about 0.28 mEq / mL, or from about 0.13 to about 0.28 mEq / mL, or from about 0.14 to about 0.28 mEq / mL, or from about 0.15 to about 0.28 mEq / mL, or from about 0.16 to about 0.28 mEq / mL, or from about 0.17 to about 0.28 mEq / mL, or from about 0.18 to about 0.28 mEq / mL, or from about 0.19 to about 0.28 mEq / mL, or from about 0.2 to about 0.28 mEq / mL, or from about 0.21 to about 0.28 mEq / mL, or from about 0.22 to about 0.28 mEq / mL, or from about 0.23 to about 0.28 mEq / mL, or from about 0.24 to about 0.28 mEq / mL, or from about 0.25 to about 0.28 mEq / mL, or from about 0.26 to about 0.28 mEq / mL, or from about 0.27 to about 0.28 mEq / mL, or from about 0.1 to about 0.27 mEq / mL, or from about 0.11 to about 0.27 mEq / mL, or from about 0.12 to about 0.27 mEq / mL, or from about 0.13 to about 0.27 mEq / mL, or from about 0.14 to about 0.27 mEq / mL, or from about 0.15 to about 0.27 mEq / mL, or from about 0.16 to about 0.27 mEq / mL, or from about 0.17 to about 0.27 mEq / mL, or from about 0.18 to about 0.27 mEq / mL, or from about 0.19 to about 0.27 mEq / mL, or from about 0.2 to about 0.27 mEq / mL, or from about 0.21 to about 0.27 mEq / mL, or from about 0.22 to about 0.27 mEq / mL, or from about 0.23 to about 0.27 mEq / mL, or from about 0.24 to about 0.27 mEq / mL, or from about 0.25 to about 0.27 mEq / mL, or from about 0.26 to about 0.27 mEq / mL, or from about 0.1 to about 0.26 mEq / mL, or from about 0.11 to about 0.26 mEq / mL, or from about 0.12 to about 0.26 mEq / mL, or from about 0.13 to about 0.26 mEq / mL, or from about 0.14 to about 0.26 mEq / mL, or from about 0.15 to about 0.26 mEq / mL, or from about 0.16 to about 0.26 mEq / mL, or from about 0.17 to about 0.26 mEq / mL, or from about 0.18 to about 0.26 mEq / mL, or from about 0.19 to about 0.26 mEq / mL, or from about 0.2 to about 0.26 mEq / mL, or from about 0.21 to about 0.26mEq / mL, or from about 0.22 to about 0.26 mEq / mL, or from about 0.23 to about 0.26 mEq / mL, or from about 0.24 to about 0.26 mEq / mL, or from about 0.25 to about 0.26 mEq / mL, or from about 0.1 to about 0.25 mEq / mL, or from about 0.11 to about 0.25 mEq / mL, or from about 0.12 to about 0.25 mEq / mL, or from about 0.13 to about 0.25 mEq / mL, or from about 0.14 to about 0.25 mEq / mL, or from about 0.15 to about 0.25 mEq / mL, or from about 0.16 to about 0.25 mEq / mL, or from about 0.17 to about 0.25 mEq / mL, or from about 0.18 to about 0.25 mEq / mL, or from about 0.19 to about 0.25 mEq / mL, or from about 0.2 to about 0.25 mEq / mL, or from about 0.21 to about 0.25 mEq / mL, or from about 0.22 to about 0.25 mEq / mL, or from about 0.23 to about 0.25 mEq / mL, or from about 0.24 to about 0.25 mEq / mL, or from about 0.1 to about 0.24 mEq / mL, or from about 0.11 to about 0.24 mEq / mL, or from about 0.12 to about 0.24 mEq / mL, or from about 0.13 to about 0.24 mEq / mL, or from about 0.14 to about 0.24 mEq / mL, or from about 0.15 to about 0.24 mEq / mL, or from about 0.16 to about 0.24 mEq / mL, or from about 0.17 to about 0.24 mEq / mL, or from about 0.18 to about 0.24 mEq / mL, or from about 0.19 to about 0.24 mEq / mL, or from about 0.2 to about 0.24 mEq / mL, or from about 0.21 to about 0.24 mEq / mL, or from about 0.22 to about 0.24 mEq / mL, or from about 0.23 to about 0.24 mEq / mL, or from about 0.1 to about 0.23 mEq / mL, or from about 0.11 to about 0.23 mEq / mL, or from about 0.12 to about 0.23 mEq / mL, or from about 0.13 to about 0.23 mEq / mL, or from about 0.14 to about 0.23 mEq / mL, or from about 0.15 to about 0.23 mEq / mL, or from about 0.16 to about 0.23 mEq / mL, or from about 0.17 to about 0.23 mEq / mL, or from about 0.18 to about 0.23 mEq / mL, or from about 0.19 to about 0.23 mEq / mL, or from about 0.2 to about 0.23 mEq / mL, or from about 0.21 to about 0.23 mEq / mL, or from about 0.22 to about 0.23 mEq / mL, or from about 0.1 to about 0.22 mEq / mL, or from about 0.11 to about 0.22 mEq / mL, or from about 0.12 to about 0.22 mEq / mL, or from about 0.13 to about 0.22 mEq / mL, or from about 0.14 to about 0.22 mEq / mL, or from about 0.15 to about 0.22 mEq / mL, or from about 0.16 to about 0.22 mEq / mL, or from about 0.17 to about 0.22 mEq / mL, or from about 0.18 to about 0.22 mEq / mL, or from about 0.19 to about 0.22 mEq / mL, or from about 0.2 to about 0.22 mEq / mL, or from about 0.21 to about 0.22 mEq / mL, or from about 0.1 to about 0.21 mEq / mL, or from about 0.11 to about 0.21 mEq / mL, or from about 0.12 to about 0.21 mEq / mL, or from about 0.13 to about 0.21 mEq / mL, or from about 0.14 to about 0.21 mEq / mL, orfrom about 0.15 to about 0.21 mEq / mL, or from about 0.16 to about 0.21 mEq / mL, or from about 0.17 to about 0.21 mEq / mL, or from about 0.18 to about 0.21 mEq / mL, or from about 0.19 to about 0.21 mEq / mL, orfrom about 0.2 to about 0.21 mEq / mL, orfrom about 0.1 to about 0.20 mEq / mL, or from about 0.11 to about 0.20 mEq / mL, or from about 0.12 to about 0.20 mEq / mL, or from about 0.13 to about 0.20 mEq / mL, or from about 0.14 to about 0.20 mEq / mL, or from about 0.15 to about 0.20 mEq / mL, orfrom about 0.16 to about 0.20 mEq / mL, orfrom about 0.17 to about 0.20 mEq / mL, or from about 0.18 to about 0.20 mEq / mL, or from about 0.19 to about 0.20 mEq / mL, or from about 0.1 to about 0.19 mEq / mL, or from about 0.11 to about 0.19 mEq / mL, or from about 0.12 to about 0.19mEq / mL, or from about 0.13 to about 0.19 mEq / mL, or from about 0.14 to about 0.19 mEq / mL, or from about 0.15 to about 0.19 mEq / mL, or from about 0.16 to about 0.19 mEq / mL, or from about 0.17 to about 0.19 mEq / mL, or from about 0.18 to about 0.19 mEq / mL, or from about 0.1 to about 0.18 mEq / mL, or from about 0.11 to about 0.18 mEq / mL, or from about 0.12 to about 0.18 mEq / mL, or from about 0.13 to about 0.18 mEq / mL, or from about 0.14 to about 0.18 mEq / mL, or from about 0.15 to about 0.18 mEq / mL, or from about 0.16 to about 0.18 mEq / mL, or from about 0.17 to about 0.18 mEq / mL, or from about 0.1 to about 0.17 mEq / mL, or from about 0.11 to about 0.17 mEq / mL, or from about 0.12 to about 0.17 mEq / mL, or from about 0.13 to about 0.17 mEq / mL, or from about 0.14 to about 0.17 mEq / mL, or from about 0.15 to about 0.17 mEq / mL, or from about 0.16 to about 0.17 mEq / mL, or from about 0.1 to about 0.16 mEq / mL, or from about 0.11 to about 0.16 mEq / mL, or from about 0.12 to about 0.16 mEq / mL, or from about 0.13 to about 0.16 mEq / mL, or from about 0.14 to about 0.16 mEq / mL, or from about 0.15 to about 0.16 mEq / mL, or from about 0.1 to about 0.15 mEq / mL, or from about 0.11 to about 0.15 mEq / mL, or from about 0.12 to about 0.15 mEq / mL, or from about 0.13 to about 0.15 mEq / mL, or from about 0.14 to about 0.15 mEq / mL, or from about 0.1 to about 0.14 mEq / mL, or from about 0.11 to about 0.14 mEq / mL, or from about 0.12 to about 0.14 mEq / mL, or from about 0.13 to about 0.14 mEq / mL, or from about 0.1 to about 0.13 mEq / mL, or from about 0.11 to about 0.13 mEq / mL, or from about 0.12 to about 0.13 mEq / mL, or from about 0.1 to about 0.12 mEq / mL, or from about 0.11 to about 0.12 mEq / mL, or from about 0.1 to about 0.11 mEq / mL, or from about 0.25 to about 2.76 mEq / mL, or from about 0.5 to about 2.76 mEq / mL, or from about 0.75 to about 2.76 mEq / mL, or from about 1 to about 2.76 mEq / mL, or from about 1 .25 to about 2.76 mEq / mL, or from about 1 .5 to about 2.76 mEq / mL, or from about 1 .75 to about 2.76 mEq / mL, or from about 2 to about 2.76 mEq / mL, or from about 2.25 to about 2.76 mEq / mL, or from about 2.5 to about 2.76 mEq / mL, or from about 2.75 to about 2.76 mEq / mL, or from about 0.25 to about 2.75 mEq / mL, or from about 0.5 to about 2.75 mEq / mL, or from about 0.75 to about 2.75 mEq / mL, or from about 1 to about 2.75 mEq / mL, or from about 1 .25 to about 2.75 mEq / mL, or from about 1 .5 to about 2.75 mEq / mL, or from about 1 .75 to about 2.75 mEq / mL, or from about 2 to about 2.75 mEq / mL, or from about 2.25 to about 2.75 mEq / mL, or from about 2.5 to about 2.75 mEq / mL, or from about 0.25 to about 2.5 mEq / mL, or from about 0.5 to about 2.5 mEq / mL, or from about 0.75 to about 2.5 mEq / mL, or from about 1 to about 2.5 mEq / mL, or from about 1 .25 to about 2.5 mEq / mL, or from about 1 .5 to about 2.5 mEq / mL, or from about 1 .75 to about 2.5 mEq / mL, or from about 2 to about 2.5 mEq / mL, or from about 2.25 to about 2.5 mEq / mL, or from about 0.25 to about 2.25 mEq / mL, or from about 0.5 to about 2.25 mEq / mL, or from about 0.75 to about 2.25 mEq / mL, or from about 1 to about 2.25 mEq / mL, or from about 1 .25 to about 2.25 mEq / mL, or from about 1 .5 to about 2.25 mEq / mL, or from about 1 .75 to about2.25 mEq / mL, orfrom about 2 to about 2.25 mEq / mL, orfrom about 0.25 to about2.0 mEq / mL, or from about 0.5 to about 2.0 mEq / mL, or from about 0.75 to about 2.0 mEq / mL, or from about 1 toabout 2.0 mEq / mL, or from about 1 .25 to about 2.0 mEq / mL, or from about 1 .5 to about 2.0 mEq / mL, or from about 1 .75 to about 2.0 mEq / mL, or from about 0.25 to about 1 .75 mEq / mL, or from about 0.5 to about 1.75 mEq / mL, or from about 0.75 to about 1.75 mEq / mL, or from about 1 to about 1.75 mEq / mL, or from about 1 .25 to about 1 .75 mEq / mL, or from about 1 .5 to about 1 .75 mEq / mL, or from about 0.25 to about 1 .5 mEq / mL, or from about 0.5 to about 1 .5 mEq / mL, or from about 0.75 to about 1 .5 mEq / mL, or from about 1 to about 1 .5 mEq / mL, or from about 1 .25 to about 1 .5 mEq / mL, or from about 0.25 to about 1.25 mEq / mL, or from about 0.5 to about 1.25 mEq / mL, or from about 0.75 to about 1 .25 mEq / mL, or from about 1 to about 1 .25 mEq / mL, or from about 0.25 to about 1 .0 mEq / mL, or from about 0.5 to about 1 .0 mEq / mL, or from about 0.75 to about 1 .0 mEq / mL, or from about 0.25 to about 0.75 mEq / mL, or from about 0.5 to about 0.75 mEq / mL, or from about 0.25 to about 0.5 mEq / mL, or 0.1 , 0.11 , 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21 , 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.3, 0.31 , 0.32, 0.33, 0.34, 0.35, 0.5, 0.75, 1 , 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 2.76 mEq / mL.

[0115] According to an embodiment, the anionic functional groups may further comprise 1) anionic functional groups providing a cross-link between the cross-linked molecules of a polyhydroxylic polymer, or 2) anionic functional groups providing a negative charge to the microparticles for interacting ionically with the positively charged drug and a cross-link between the cross-linked molecules of a polyhydroxylic polymer.

[0116] According to an embodiment, in the pharmaceutical composition of the present invention, where the polyhydroxylic polymer is a polyvinyl alcohol (PVA), a native starch (S) or a combination thereof, and the anionic functional groups comprise a metaphosphate group, the metaphosphate group may comprise 1) first metaphosphate groups providing a negative charge to the microparticles for interacting ionically with the positively charged drug; 2) second metaphosphate groups providing a cross-link between the cross-linked molecules of a polyhydroxylic polymer; and 3) third metaphosphate groups providing a negative charge to the microparticles for interacting ionically with the positively charged drug and providing a cross-link between the cross-linked molecules of a polyhydroxylic polymer.

[0117] According to an embodiment, in the pharmaceutical composition of the present invention, where the polyhydroxylic polymer is a carboxymethylstarch (CMS), and the anionic functional groups comprise a carboxyl group and a metaphosphate group, and the metaphosphate group may comprise 1) first metaphosphate groups providing a negative charge to the microparticles for interacting ionically with the positively charged drug; 2) second metaphosphate groups providing a cross-link between the cross-linked molecules of a polyhydroxylic polymer; and 3) third metaphosphate groups providing a negative charge to the microparticles for interacting ionically with the positivelycharged drug and providing a cross-link between the cross-linked molecules of a polyhydroxylic polymer.Positively charged drugs

[0118] According to embodiments, the positively charged drug loaded on the microparticles may be an anesthetic agent, a chemotherapeutic agent, a nonsteroidal anti-inflammatory drug, a narcotic, an antibiotic, or combinations thereof.

[0119] In embodiments, the reconstituted microparticles may be loaded (i.e., have a drug loading capacity) of from about 0.1 mg of drug to about 3600 mg of drug per g of microparticles, or from about 0.1 to about 1 mg, or from about 0.2 to about 1 mg, or from about 0.3 to about 1 mg, or from about 0.4 to about 1 mg, or from about 0.5 to about 1 mg, or from about 0.6 to about 1 mg, or from about 0.7 to about 1 mg, or from about 0.8 to about 1 mg, or from about 0.9 to about 1 mg, or from about 1 to about 10 mg, or from about 2 to about 10 mg, or from about 3 to about 10 mg, or from about 4 to about 10 mg, or from about 5 to about 10 mg, or from about 6 to about 10 mg, or from about 7 to about 10 mg, or from about 8 to about 10 mg, or from about 9 to about 10 mg, or from about 10 to about 100 mg, or from about 20 to about 100 mg, or from about 30 to about 100 mg, or from about 40 to about 100 mg, or from about 50 to about 100 mg, or from about 60 to about 100 mg, or from about 70 to about 100 mg, or from about 80 to about 100 mg, or from about 90 to about 100 mg, or about 100 mg to about 3600 mg, or about 500 mg to about 3600 mg, or about 1000 mg to about 3600 mg, or about 1500 mg to about 3600 mg, or about 2000 mg to about 3600 mg, or about 2500 mg to about 3600 mg, or about 3000 mg to about 3600 mg, or about 3500 mg to about 3600 mg, or about 100 mg to about 3500 mg, or about 500 mg to about 3500 mg, or about 1000 mg to about 3500 mg, or about 1500 mg to about 3500 mg, or about 2000 mg to about 3500 mg, or about 2500 mg to about 3500 mg, or about 3000 mg to about 3500 mg, or about 100 mg to about 3000 mg, or about 500 mg to about 3000 mg, or about 1000 mg to about 3000 mg, or about 1500 mg to about 3000 mg, or about 2000 mg to about 3000 mg, or about 2500 mg to about 3000 mg, or about 100 mg to about 2500 mg, or about 500 mg to about 2500 mg, or about 1000 mg to about 2500 mg, or about 1500 mg to about 2500 mg, or about 2000 mg to about 2500 mg, or about 100 mg to about 2000 mg, or about 500 mg to about 2000 mg, or about 1000 mg to about 2000 mg, or about 1500 mg to about 2000 mg, or about 100 mg to about 1500 mg, or about 500 mg to about 1500 mg, or about 1000 mg to about 1500 mg, or about 100 mg to about 1000 mg, or about 500 mg to about 1000 mg, or about 100 mg to about 500 mg, or 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92 mg, 93 mg, 94 mg, 95 mg, 96 mg, 97 mg, 98 mg, 99 mg, 100 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 2000 mg, 2500 mg, 3000 mg, 3500 mg, 3600 mg of drug per g of microparticles.Anesthetic

[0120] While commercially available loadable microparticles are designed to carry small quantities of potent chemotherapeutic agents, such as doxorubicin, the microparticles of the present invention allow loading of large quantities of other drugs, such as lidocaine. This high-loading capacity property allows to use less potent drugs or drugs with a relatively short half-life that require a larger amount to provide sustained therapeutic effect. For example, it would allow the use of lidocaine instead of bupivacaine. Bupivacaine is a more potent anesthetic than lidocaine but is also far more toxic. According to an embodiment, the anesthetic agent loaded on the microparticle may be (but not limited to) lidocaine, bupivacaine, ropivacaine, or a combination thereof. Preferably, the anesthetic agent loaded by the microparticle is lidocaine. According to embodiments, when the polyhydroxylic polymer is CLPVA-MP, it may have a drug loading capacity up to about 550 mg of lidocaine per mL of reconstituted microparticles. According to another embodiment, when the polyhydroxylic polymer is CLS-MP, the its drug loading capacity was up to about 550 mg of lidocaine per mL of reconstituted microparticles.

[0121] With embodiments of the present invention, the analgesic effect of lidocaine lasts for at least two hours in the patient upon administration.

[0122] The use of the microparticles of the present invention to transport anesthetic agents will make it possible to replace costly and invasive anesthesia methods such as continuous epidural anesthesia, which require human and material resources. It could also make it possible to perform these procedures on an outpatient basis, without hospitalizing patients - a major advantage in terms of resource utilization.Other drugs

[0123] According to another embodiment, the chemotherapeutic agent may be adriamycin, irinotecan, epirubicin, or combinations thereof.

[0124] According to another embodiment, the angiogenesis inhibitor is bevacizumab.

[0125] According to another embodiment, the nonsteroidal anti-inflammatory drug is ketorolac.

[0126] According to another embodiment, the narcotic is tramadol, oxycodone, or combinations thereof.

[0127] According to another embodiment, the antibiotic is ciprofloxacin, tetracycline, clindamycin, or combinations thereof.Pharmaceutical compositions

[0128] The amount of active ingredient (i.e., the positively charged drug[s]) that may be combined with the microparticles to produce a dosage form will vary depending upon the treated target and the particular mode of administration. For example, a formulation may conveniently contain from about 0.5 mg to about 1 g , or about 0.5 mg to about 500 mg, or about 0.5 mg to about 50 mg, or about 0.5 mg to about 5 mg, or about 5 mg to about 2 g, or about 5 mg to about 500 mg, or about 5 mg to about 50 mg, or about 50 mg to about 2 g, or about 50 mg to about 500 mg, or about 500 mg to about 2 g of active agent, formulated with an appropriate and acceptable amount of generally recognized as safe (“GRAS”) materials which may vary from about 5 to about 95 percent of the total composition. Unit dosage forms will generally contain between about 0.001 mg to about 1000 mg, or about 0.01 mg to about 1000 mg, or about 0.1 mg to about 1000 mg, or about 1 mg to about 1000 mg, or about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg, or about 0.001 mg to about 100 mg, or about 0.01 mg to about 100 mg, or about 0.1 mg to about 100 mg, or about 1 mg to about 100 mg, or about 10 mg to about 100 mg, or about 0.001 mg to about 10 mg, or about 0.01 mg to about 10 mg, or about 0.1 mg to about 10 mg, or about 1 mg to about 10 mg, or about 0.001 mg to about 1 mg, or about 0.01 mg to about 1 mg, or about 0.1 mg to about 1 mg, or about 0.001 mg to about 0.1 mg, or about 0.01 mg to about 0.1 mg, or about 0.001 mg to about 0.01 mg of the active ingredient, typically 0.001 mg, 0.005 mg, 0.025 mg, 0.1 mg, 0.5 mg, 2.5 mg, 5.0 mg, 10 mg, 30 mg, 60 mg, 100 mg, 300 mg, 600 mg, 1000 mg, 2000 mg or any dose in-between.

[0129] It is understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

[0130] These and other ways in which specific dosage forms provided herein will vary from one another will be readily apparent to those skilled in the art. See e.g., Remington’s Pharmaceutical Sciences, 23rded., Mack Publishing, Easton, Pa (2020). In practice, pharmaceutical compositions of this invention can be combined as the active ingredient ionically interacting with the polymeric granule of the invention through ionic interactions, in intimate admixture with pharmaceutical excipients, carrier,or diluents according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for parenteral administration (including intravenous, intradermal, subcutaneous, bolus injection, intramuscular, or intraarterial). Thus, the pharmaceutical compositions of the present invention can be presented as discrete units (dosage forms). Further, the compositions can be presented as a powder, as granules, as coated sustained-release particles, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion or as a water-in-oil liquid emulsion, liposomes, or nanosuspension. In addition to the common dosage forms set out above, the microparticles may also be administered by controlled- or modified-release formulation, and / or delivery devices. The compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient (here in contact with the microparticles) with the excipients or carriers that constitute one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient (and here the polymeric granules) with liquid carriers / excipients or finely divided solid carriers / excipients or both. The product can then be conveniently shaped into the desired presentation.

[0131] Pharmaceutical compositions of the present invention suitable for parenteral administration (including intravenous, intramuscular, subcutaneous, ocular, and intraarterial) may be prepared as solutions or suspensions of the active compounds in injectable ingredients. Parenteral dosage forms are preferably sterile or capable of being sterilized prior to administration to a patient. Non-limiting examples of suitable vehicles include Water for Injection USP; Dextrose Injection; Sodium Chloride Injection and lactated Ringer’s Injection. A suitable surfactant can be included such as, for example, polysorbate 80. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, ethyl alcohol, polypropylene glycol and mixtures thereof in non-aqueous vehicles such as oils (e.g., corn oil, sesame oil, isopropyl myristate). An antioxidant to help stabilize the formulation can be Vit C palmitate. Further, a preservative can be included to prevent the detrimental growth of microorganisms.

[0132] Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile, non-irritating with addition of tonicity agents and must be effectively fluid for easy syringeability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms as bacteria and fungi with preservative agents such as benzalkonium chloride, chlorobutanol, methylparaben, propylparaben, edetate disodium, sorbic acid, or other agents known to those skilled in the art. Pharmaceutical compositions of the present invention can be in a form suitable for topical application locally to the skin and its adnexa or to a variety of mucous surfaces.Such forms may be, for example, an aerosol, patch, cream, ointment, lotion, dusting powder, emulsions, or the like. The routes that can be used include nasal, sublingual, ocular, buccal, aural vaginal, or rectal. Further, the compositions can be in a form suitable for use in transdermal or intradermal micro-needle devices. These formulations may be prepared, utilizing microparticles of this invention, via conventional processing methods. As an example, a lotion, cream, or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt / wt % to about 30 wt / wt % of the compound, to produce a cream, lotion, or ointment having a desired consistency. Examples of typical excipients include water, acetone, ethanol, ethylene glycol, propylene glycol, isopropyl myristate, mineral oil, and mixtures thereof. Moisturizers such as occlusives, humectants, or emollients can also be added to the pharmaceutical compositions and dosage forms if desired. The pH of a pharmaceutical composition or dosage form may also be adjusted to improve delivery. Dosage forms suitable for treating mucosal tissues within the oral cavity can be formulated as mouthwashes or as oral gel.

[0133] Pharmaceutical compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid or liquid or spray. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in moulds.

[0134] In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient. Addition of preservatives such as antioxidants are widely acceptable in pharmaceutical arts for long-term storage in order to determine characteristics such as shelf life or stability of formulations over time (See e.g., Jens T. Carstensen, Drug stability: Principles & Practice. 2ndEd., Marcel Dekker, NY, NY. 1995, pp 379-80).Use of the invention

[0135] According to another embodiment, there is disclosed a method for vascular embolization, radio-embolization, or both, of a blood vessel in a patient in need thereof comprising administering to the patient the pharmaceutical composition of the present invention.

[0136] In another embodiment there is disclosed a method for the management of pain during vascular embolization, radio-embolization, or both, of a blood vessel in a patient in need thereof comprising administering to the patient the pharmaceutical composition of the present invention.

[0137] According to another embodiment, the pharmaceutical composition of the present invention may be for use in vascular embolization, radio-embolization, or both in a patient in need thereof.

[0138] According to another embodiment, the pharmaceutical composition of the present invention may be for use in the management of pain during vascular embolization, radio-embolization, or both in a patient in need thereof.

[0139] In another embodiment there is disclosed a method for vascular embolization, radioembolization, or both, of a blood vessel in a patient in need thereof comprising administering to the patient the pharmaceutical composition of the present invention.

[0140] According to another embodiment, the pharmaceutical composition and the method of the present invention may be for use in the context of vascular embolization of uterine arteries.

[0141] According to another embodiment, the pharmaceutical composition and the method of the present invention may be for use for the treatment of uterine fibroids.

[0142] The present invention will be more readily understood by referring to the following examples which are given to illustrate the invention rather than to limit its scope.EXAMPLESMaterials

[0143] Polyvinyl alcohol (PVA) 13,000-23,000 (MW), PVA 130000 (MW), sodium monochloroacetate (SMCA), sodium trimetaphosphate (STMP) and other chemicals were all reagent grade and used as received from Millipore Sigma (Burlington, Massachusetts, USA).

[0144] Hylon VII® (~70% amylose)(native starch, 100-150 kDa) was from Ingredion™ (Westchester, IL, USA).

[0145] Lidocaine hydrochloride monohydrate was purchased from Galenova™ and bupivacaine hydrochloride from Pfizer™.EXAMPLE 1PREPARATION OF THE PVA-CL BEADS BY WATER-WATER EMULSION

[0146] The beads were prepared using a water-in-water emulsion method with some modifications. Briefly an aqueous continuous phase was obtained and added in the dispersed phase.

[0147] To obtain the aqueous continuous phase, 80 g of polyethylene glycol 20,000 (MW) was added to 200 mL of water and this mixture was maintained under stirring (500 rpm) in a water bath at 55°C (continuous phase).

[0148] A quantity of 5 g of the PVA solution was separately dissolved at 75°C in 50 mL water to obtain a 10% PVA solution (w / v). This solution was added at room temperature in 25 mL of 1 M NaOH with stirring (dispersed phase). Then, the dispersed phase was added to the continuous phase.

[0149] Once the PVA solution was dispersed in the continuous phase, an aqueous solution of 10 mL of cross-linker STMP (PVA: STMP 4:1 m / m) was added to the emulsion with stirring for 30 min. The subsequent step is the neutralization of the emulsion with HCI or acetic acid until the pH reached 7. During this step, the emulsion remained stirred for 2 h at room temperature at 800 rpm and then left for 18 h to allow adequate sedimentation of the microparticles of cross-linked PVA (PVA-CL). Finally, the collected microparticles of beaded PVA-CL(B) where B stands for “beaded” were washed with amounts of acetone-water (50:50, 60:40, 80:20,100:0), then dried with acetone on the filter of a Buchner funnel, under vacuum. The dried microparticles have been then sieved, retaining particles in the range 100-700 pm, preferably in the range 300-500 pm and stored in sealed vials until use.

[0150] For PVA-CL (B), 1 g of dry product generates 10.7 mL gel bed. The Swelling volume is: 10.7 mL gel / g (dry product).EXAMPLE 2PREPARATION OF THE CLPVA-MP BEADS IN ONE AQUEOUS PHASE

[0151] Differently to the example 1 (PEG emulsion), this example 2 describes PVA beads cross-linked with STMP directly in water medium based on the ability of STMP, the cross-linker agent, to react and bind chains when the pH was increased at pH 10.

[0152] A quantity of 10 g of PVA (130 kDa) was added to 100 mL of distilled water under stirring (450 rpm) on a water bath at 80°C until complete dissolution, forming a PVA 10 % solution.

[0153] After dissolution of the PVA, 1 g of the SMTP cross-linking agent was added to the PVA solution under continuous stirring at 500 rpm at 55°C for 1 h. The reaction medium was then cooled-down to room temperature. The cooled reaction medium of PVA and STMP was then extruded from a needle (inner diameter: 210 pm) as droplets, into an aqueous solution of NaOH (pH 10), under stirring (450 rpm) for 30 min, to form the cross-linked CLPVA-MP. Then the reaction medium was neutralized with HC1 1 M until pH reached 7. Finally, the beads were collected, washed with water, and dried first with 25 mL of acetone and then kept overnight at room temperature. The dried microparticles,termed CLPVA-MP10, were stored in sealed vials until use. The number (10) is the conventional CLD, meaning that the cross-linker was in a ratio of 10 % versus the amount of polymer cross-linked.

[0154] Similarly, an amount of CLPVA-MP5 was obtained in the same conditions, but with only a half of the amount of STMP (in this example 0.5 g STMP added for crosslinking).

[0155] The MP stands fo the metaphosphate anionic group generated by the cross-linking.EXAMPLE 3STARCH MODIFICATIONS TO OBTAIN CMS MICROSPHERES

[0156] 3.1 . Starch carboxymethylation (CMS1) was done as previously described [Massicotte et al, 2008], Briefly, 140 g starch were suspended in 340 mL water at 55 °C under stirring. Then, 320 mL of 2M NaOH were added. After20 min of gelatinization, 70 g of sodium monochloroacetate (SMCA) were added under stirring. The mixture was kept under stirring for 1 h, cooled, neutralized with acetic acid, and precipitated with aqueous methanol (60% v / v). The precipitate was washed by decantation with aqueous methanol (60% v / v) until the conductivity was below 50 microSiemens (pS)and finally with acetone, filtered and exposed to vacuum for drying.

[0157] 3.2. CMS2 was obtained by heating the starch suspension at 90 °C for 1 h before adding 2M NaOH and proceeding with carboxymethylation as for CMS1 except that the amount of SMCA directly in powder form was doubled.3.3. CMS was also cross-linked to obtain CMS-CL20 using the same gelatinization parameters as for starch by adding sodium trimetaphosphate (STMP) at 20 g / 100 g of starch. CMS-CL10 CMS was obtained in similar conditions but using only half the volume of water, to obtain the called CMS-CL10.

[0158] The Degree of Substitution (DS) was determined by titration of carboxylic groups and expressed as the number of substituted hydroxyls on each glucose unit (maximal theoretical value: DS = 3).

[0159] The CMS derivatives presented DS values of 0.15, 0,19, 0.22, 0.30 fitting well those described in literature, up to 0.35 (Massicotte et al, 2008).

[0160] For cross-linked polymers, the cross-linking degree (CLD) was defined as the amount of STMP used to cross-link 100 g polymer.EXAMPLE 4STARCH CROSS-LINKING WITH STMP TO OBTAIN (CLS-MP)

[0161] An amount of 20 g Hylon® VII (native starch) was gradually incorporated into 60 mL of distilled water under continuous stirring at 300 rpm at room temperature, to avoid the formation ofstarch aggregates. Then, gelatinization was performed by adding 1 g of NaOH, to maintain the pH at 10 and increasing the temperature to 55°C, under continuous stirring (300 rpm, 30 min). Then, 1 or 2 g of STMP (to obtain concentrations of 5% w / w or 10% w / w STMP) were added under stirring at 600 rpm, while maintaining the temperature at 55°C. After 2 hours of reaction, the pH was adjusted to pH 7.0 by addition of HCI. Finaly, the materials, hereto called CLS-MP5 or CLS-MP10 were washed with distilled water (two times reactional volume) to remove soluble materials and then washed several times with 60% acetone until a low conductivity of <50 microSiemens (pS) / cm. The numbers (5, 10) represent the conventional cross-linking degree expressed as percentage of cross-linker (STMP) used to cross-link 100 g of starch. The CLS-MP5 and the CLS-MP10 samples were placed on a Buchner filter and washed with 100% acetone to remove water. The materials were then dried in an oven at 40°C for 8 hours, providing the corresponding dry CLS-MP5 and the CLS-MP10 microparticles.EXAMPLE 5GRANULATION OF THE CLS-MP BEADS

[0162] The wet granulation was used to prepare microbeads of CLS-MP. The objective was to increase the size and to reinforce the CLS-MP such as to be more adequate for embolization. The process was performed using a Fukae Powtec™ High Speed Mixer. A three-bladed impeller was mounted on the bottom of the 2 L bowl and a chopper was placed on the bowl side opposite to the binder addition nozzle. A dry mass of 300 g of CLS-MP5 or CLS-MP10 was used for each batch and 220 mL of ultrapure water was used as a liquid binder at 23°C. The dry powder was first mixed for 1 min without water addition. Then the addition of water was gradually started under continuous mixing for 3 min. The speed of the impeller (1000 rpm) and the chopper (2000 rpm) were maintained constant during the procedure, at a constant temperature of 23°C. Granules were oven dried at 40°C for more than 24 h.EXAMPLE 6CHARACTERIZATION OF MICROPARTICLESSwelling volume

[0163] An amount 1 g of microbeads was swollen in distilled water or in a physiological solution, directly in a graduated cylinder, homogenized several times and left to settle until having a constant volume. The swelling volume is expressed as swollen volume (mL gel bed) / g of dry product: mL gel / g.

[0164] The swelling volume of CLPVA-MP10 was 5.35 mLgeibed / g.

[0165] Thus 187 mg dry microparticles will generate 1 mL gel bed

[0166] The swelling volume of CLS-MP5 and of CLS-MP10 was for both of 6.00 mLgei ed / g-Granulation

[0167] The moisture (also known as humidity or as Water Content [WC]) was determined by thermogravimetry analysis (TGA) using a TGA Q500 instrument (TA Instruments, New Castle, DE, USA). The temperature was raised from 20 °C to 500 °C with a rate of 10 °C / min under high-purity nitrogen conditions. The water content (WC%) was estimated by the weight loss measured in the range of 20-105 °C.

[0168] The WC % before granulation for CLS-MP5 was of 6.30% while for the CLS-MP10 was of 4.98%. The loss of weight corresponding to the evaporation of water for granulated CLS-MP5 and CLS-MP10 was 6.7% and 7.2% respectively.

[0169] The granulation was beneficial providing microparticles with size (swollen 500-800mm) and shape adequate for embolization (Fig. 8B and Fig. 8C).EXAMPLE 7LOADING OF LIDOCAINE ON VARIOUS MICROPARTICLES

[0170] Loading of the PVA-CL beads obtained with PEG emulsion procedure generated a retention capacity of PVA-CL of 160 mg / mL of reconstituted microparticles, a value higher than that obtained with commercial products in similar loading conditions.

[0171] To evaluate loading of lidocaine on the CLPVA-MP10 microbeads, a convenient mass of microbeads expected to generate a swollen volume equal of the volume of lidocaine solution, was used. For maximal lidocaine loading capacity of CLPVA-MP10 (i.e., saturation), considering that 187.5 mg of CLPVA-MP10 beads generates a volume of 1 mL of reconstituted material in water, an amount of 0.94 g of dry CLPVA-MP10 material was swollen in 5 mL of lidocaine at different concentrations (25, 50, 100 and 500 mg / mL) at 25 °C in physiological saline 0.9 % w / v NaCI. The various ratios CLPVA- MP10 to retained lidocaine (CLPVA-MP10 : lidocaine ratios) allowed to establish the maximal loading capacity. : the best lidocaine loading on CLPVA-MP10 microbeads. Time-course of loading was followed for loading times. At various time intervals (0, 0.25, 0.5, 0.75, 1 , 2, 4, and 24 h), 10 pL of supernatant was taken and added to 990 pL water. The absorbances were measured by spectrophotometry at 262 nm using a quartz cuvette. The amount of lidocaine was determined from a standard curve of UV absorption as a function of the concentration of the lidocaine solution.

[0172] The amount of loaded lidocaine was calculated by subtracting the unloaded lidocaine (supernatant) from the whole quantity used for loading. Maximum loading was of 550 mg lidocaine / mLof CLPVA-MP10 microparticles (2933 mg lidocaine / g CLPVA-MP10 microparticles at a loading time of at least 2h - Fig. 4 and 5).

[0173] The maximal retention capacity of CLPVA-MP10 was 550 mg / mL of reconstituted microparticles, a value higher than that obtained with commercial products DCBeads™ in similar loading conditions (Fig. 5). Maximal loading capacities were found for microparticles of CLPVA-MP10, of CLS-MP5, CLS-MP10 and the time-course showed a fast loading of about 2 h).

[0174] Alternatively, 187.5 mg of beads can be swollen in physiological saline solution prior to loading. Then, the microbeads may be collected by decantation orfiltration and immersed in a lidocaine solutions (50 - 1000 mg / mL) for adsorption under agitation for 2h.EXAMPLE 8LIDOCAINE RELEASE FROM VARIOUS ANIONIC LOADED MICROPARTICLES

[0175] The lidocaine release was followed for up to 24 h. The release patterns showed a liberation of lidocaine in physiological solution over about 2-3 h, covering the duration expected of the embolization procedure (Fig. 6 ).EXAMPLE 9LOADING OF THE CLPVA-CL10, CLS-MP5 AND CL-MP10, CMS, CMS-CL WITH BUPIVACAINE

[0176] The loading of microbeads with bupivacaine (7.5 mg / mL at 25 °C in NaCI 0.9%) was carried out in similar conditions as described above for lidocaine. The results were comparable with the loading of lidocaine at same concentration (Fig. 7).EXAMPLE 10BEHAVIOR OF LOADED MICROPARTICLES WHEN PASSED THROUGH MICROCATHETERS FOR EMBOLIZATION

[0177] A volume of about 3 mL gel bed of PVA-CL microspheres (300-500 pm beads) loaded with lidocaine was incorporated into a solution (6 mL) containing 50% Omnipaque contrast agent (GE Healthcare™) and 50 % NaCI 0.9% (w / v) under stirring to obtain a homogeneous suspension. The suspension containing the microparticles (microspheres) was passed through various 3 Fr (Renegade™ HI-FLO™) microcatheters (Hi-Flo™) with an opening of 686 pm (0.027 inch) and lengths of 105, 115, 135, 150 cm with an ease of 5 on 5 counting from very difficult 0 to very easy 5 at passage.

[0178] The obtained results (Figs. 9A, 9B) showed no deformation or fragmentation of the beads (loaded or unloaded) after passage through microcathethers.

[0179] UFE with non-spherical PVA, was used for embolization requires a mean of 2 to 4 vials of 1 mL of dry embolic agent. In a randomized study (Duvnjak et al, 2016). Previous studies reported 82 mg of lidocaine loaded per ml of DEB, and 100 mg of lidocaine loaded per gram of DEB (Tian et al, 2022). In the present disclosure, each mL of reconstituted (swollen) PVA-CL (STMP-PVA) could unexpectedly be loaded with about 550 mg of lidocaine.

[0180] CLS-MP of the present invention offers an even better option for pain management in UFE. Considering their degradability, the CLS-MP may allow a complete drug elution and also with the advantage of relief of unnecessary lasting ischemia, that with current synthetic materials remains well beyond what is needed to induce fibroid necrosis, allowing earlier return to normal life.

[0181] While preferred embodiments have been described above and illustrated in the accompanying drawings, it will be evident to those skilled in the art that modifications may be made without departing from this disclosure. Such modifications are considered as possible variants comprised in the scope of the disclosure.REFERENCES1. Keung JJ, Spies JB, Caridi TM. Uterine artery embolization: a review of current concepts. Best Pract Res Clin Obstet Gynaecol 2018;46:66-73.2. Desevaux, C., Dubreuil, P., & Lenaerts, V. (2002). Characterization of crosslinked high amylose starch matrix implants: 1. In vitro release of ciprofloxacin. Journal of controlled release, 82(V), 83-93.3. Duvnjak S, Ravn P, Green A, Andersen PE. Clinical Long-Term Outcome and Reinterventional Rate After Uterine Fibroid Embolization with Nonspherical Versus Spherical Polyvinyl Alcohol Particles. Cardiovasc Intervent Radiol. 2016 Feb;39(2):204-9. doi: 10.1007 / s00270-015-1157-5. Epub 2015 Jun 30. PMID: 26122738.4. Gross A, Albrecht T. Transarterial Chemoembolisation (TACE) with Degradable Starch Microspheres (DSM) and Anthracycline in Patients with Locally Extensive Hepatocellular Carcinoma (HCC): Safety and Efficacy. Cardiovasc Intervent Radiol. 2020 Mar;43(3):402-410. doi: 10.1007 / s00270-019-02364- w. Epub 2019 Nov 8. PMID: 31705244.5. Fuchs K, Duran R, Denys A, Bize PE, Borchard G, Jordan O. Drug-eluting embolic microspheres for local drug delivery - State of the art. J Control Release. 2017 Sep 28;262:127-138. doi: 10.1016 / j.jconrel.2017.07.016. Epub 2017 Jul 11 . PMID: 28710006.6. Massicotte L. P., Bailie W. E., Mateescu M. A., Carboxylated high amylose starch as pharmaceutical excipients. Int. J. Pharm., 2008, 356, 212-223 (20).

Claims

CLAIMS:1 . A pharmaceutical composition comprising: a plurality of microparticles loaded with a positively charged drug, said microparticles comprising cross-linked molecules of a polyhydroxylic polymer comprising hydroxyl groups and having anionic functional groups comprising carboxylic, phosphate, metaphosphate, or sulfonate functional groups, or combinations thereof, said anionic functional groups providing a negative charge to said microparticles, and interacting ionically with said positively charged drug; said cross-linked molecules of a polyhydroxylic polymer having a degree of substitution of hydroxyl groups of about 0.1 to about 1 .5, and an exchange capacity of from about 0.1 to 2.76 mEq of said anionic functional groups per mL of said cross-linked molecules of a polyhydroxylic polymer , said plurality of microparticles being operable to provide a size distribution of about 45 pm to 1200 pm, and a pharmaceutically acceptable excipient.

2. The pharmaceutical composition of claim 1 , wherein said polyhydroxylic polymer is a polyvinyl alcohol (PVA), a native starch (S), or a carboxymethylstarch (CMS), or a combination thereof.

3. The pharmaceutical composition of claim 1 or 2, wherein said polyhydroxylic polymer is PVA having a molecular weight of about 13 to about 130 kDa.

4. The pharmaceutical composition of any one of claim 1-3, wherein said microparticles are spherical microparticles, non-spherical microparticles or a combination thereof.

5. The pharmaceutical composition of claim 2, wherein said CMS has a molecular weight of about 50 to about 150 kDa.

6. The pharmaceutical composition of claim 2 or 5 wherein said CMS has a degree of substitution of about 0.1 to about 0.3.

7. The pharmaceutical composition of any one of claims 1 - 6, wherein said cross-linked molecules of a polyhydroxylic polymer has a cross-linking degree of about 1 % to about 10 %.

8. The pharmaceutical composition of any one of claims 1 to 6, wherein said anionic functional groups comprises a metaphosphate group.

9. The pharmaceutical composition of any one of claims 1 to 7, wherein said polyhydroxylic polymer is cross-linked with sodium trimetaphosphate (STMP), sodium hexametaphosphate (SHMP), or a combination thereof.

10. The pharmaceutical composition of any one of claims 1 to 9, wherein said anionic functional groups further comprise1) anionic functional groups providing a cross-link between said cross-linked molecules of a polyhydroxylic polymer, or2) anionic functional groups providing a negative charge to said microparticles for interacting ionically with said positively charged drug and a cross-link between said cross-linked molecules of a polyhydroxylic polymer.11 . The pharmaceutical composition of any one of claims 1-4 and 7-9, wherein said polyhydroxylic polymer is a polyvinyl alcohol (PVA), a native starch (S) or a combination thereof, and said anionic functional groups comprise a metaphosphate group, wherein said metaphosphate group comprises1) first metaphosphate groups providing a negative charge to said microparticles for interacting ionically with said positively charged drug;2) second metaphosphate groups providing a cross-link between said cross-linked molecules of a polyhydroxylic polymer; and3) third metaphosphate groups providing a negative charge to said microparticles for interacting ionically with said positively charged drug and providing a cross-link between said cross-linked molecules of a polyhydroxylic polymer.

12. The pharmaceutical composition of any one of claims 1-2, and 4-9, wherein said polyhydroxylic polymer is a carboxymethylstarch (CMS), and said anionic functional groups comprise a carboxyl group and a metaphosphate group, and wherein said metaphosphate group comprises1) first metaphosphate groups providing a negative charge to said microparticles for interacting ionically with said positively charged drug;2) second metaphosphate groups providing a cross-link between said cross-linked molecules of a polyhydroxylic polymer; and3) third metaphosphate groups providing a negative charge to said microparticles for interacting ionically with said positively charged drug and providing a cross-link between said cross-linked molecules of a polyhydroxylic polymer.

13. The pharmaceutical composition of any one of claims 1 to 2, wherein said plurality of microparticles is operable to provide size distribution of about 100 pm to 900 pm.

14. The pharmaceutical composition of claim 13, wherein said plurality of microparticles is operable to provide a preferred size distribution of about 300 pm to 900 pm.

15. The pharmaceutical composition of claim 14, wherein said plurality of microparticles is enabled to provide a size distribution of about 500 pm to 800 pm.

16. The pharmaceutical composition of any one of claims 1 to 15, wherein said positively charged drug is an anesthetic agent, a chemotherapeutic agent, a narcotic, a nonsteroidal anti-inflammatory drug, an antibiotic, an angiogenesis inhibitor or combinations thereof.

17. The pharmaceutical composition of claim 16, wherein said anesthetic agent is lidocaine, bupivacaine, ropivacaine, or a combination thereof.

18. The pharmaceutical composition of claim 17, wherein the anesthetic agent is lidocaine.

19. The pharmaceutical composition of claim 18, wherein said polyhydroxylic polymer is PVA, CMS, CLS or a combination thereof, and has a drug loading capacity of 3600mg of lidocaine per gram of cross-linked molecules of a polyhydroxylic polymer.

20. The pharmaceutical composition of claim 16, wherein said chemotherapeutic agent is adriamycine, irinotecan, epirubicine, or combinations thereof.

21. The pharmaceutical composition of claim 16, wherein said nonsteroidal anti-inflammatory drug is ketorolac.

22. The pharmaceutical composition of claim 16, wherein said narcotic is tramadol, oxycodone, or combinations thereof.

23. The pharmaceutical composition of claim 16, wherein said antibiotic is ciprofloxacin, tetracycline, clindamycine, or combinations thereof.

24. The pharmaceutical composition of claim 16, wherein said angiogenesis inhibitor is bevacizumab.

25. The pharmaceutical composition of any one of claims 1-18 and 20-23, wherein said plurality of microparticles have loaded thereon from about 0.1 to about 3600 mg of said positively charged drug per g of microparticles.

26. The pharmaceutical composition of any one of claims 17 to 19, for use in vascular embolization, radio-embolization, or both in a patient in need thereof.

27. The pharmaceutical composition of any one of claims 17 to 19, for use in the management of pain during or after vascular embolization, radio-embolization, or both in a patient in need thereof.

28. A method for vascular embolization, radio-embolization, or both, of a blood vessel in a patient in need thereof comprising administering to said patient of the pharmaceutical composition of any one of claims 17 to 19.

29. A method forthe management of pain during and after vascular embolization, radio-embolization, or both, of a blood vessel in a patient in need thereof comprising administering to said patient the pharmaceutical composition of any one of claims 17 to 19.

30. The pharmaceutical composition for use of claim 26 or 27, or the method of claims 28 or 29, wherein said vascular embolization is vascular embolization of uterine arteries.31 . The pharmaceutical composition or the method of claim 30, wherein said vascular embolization of uterine arteries is for the treatment of uterine fibroids.

32. The pharmaceutical composition of claim 2, wherein said cross-linked molecules of a polyhydroxylic polymer are a polyvinyl alcohol cross-linked polymer having from about 0.1 to about 1.0 mEq of said anionic functional group per mL of said cross-linked molecules of a polyhydroxylic polymer on a dry basis, preferably 0.33 mEq / mL.

33. The pharmaceutical composition of claim 2, wherein said cross-linked molecules of a polyhydroxylic polymer are a carboxymethylstarch cross-linked polymer having from about 0.1 to about 2.76 mEq of said anionic functional groups per mL of said cross-linked molecules of a polyhydroxylic polymer on a dry basis, preferably 0.27 mEq / mL.

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