CN117120020A - Implantable medical device for delivery of nucleic acid encapsulated particles - Google Patents
Implantable medical device for delivery of nucleic acid encapsulated particles Download PDFInfo
- Publication number
- CN117120020A CN117120020A CN202280026287.8A CN202280026287A CN117120020A CN 117120020 A CN117120020 A CN 117120020A CN 202280026287 A CN202280026287 A CN 202280026287A CN 117120020 A CN117120020 A CN 117120020A
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- Prior art keywords
- medical device
- implantable medical
- lipid
- acid
- polymer matrix
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
An implantable medical device is provided. The device includes a drug release layer, wherein the drug release layer comprises particles dispersed within a polymer matrix. The lipid particles include a carrier component comprising a carrier (e.g., peptide, protein, carbohydrate, lipid, polymer, etc.) and encapsulating a nucleic acid, wherein the polymer matrix comprises an ethylene vinyl acetate copolymer. The ratio of the melting temperature of the ethylene-vinyl acetate copolymer to the melting temperature of the support is about 2 ℃ per DEG C or less.
Description
Cross Reference to Related Applications
The application claims the benefit of U.S. provisional patent application Ser. No. 63/167,718, 30 on 3 of 2021, and U.S. provisional patent application Ser. No. 63/179,627, 26 on 4 of 2021, which are incorporated herein by reference in their entireties.
Background
Nucleic acids, such as mRNA and siRNA, have recently become the focus of a number of gene therapy therapies (e.g., tumor therapy, vaccines, etc.). For example, ribonucleic acids (e.g., mRNA) are not stably integrated into the genome of transfected cells as compared to DNA, thus eliminating the concern that the introduced genetic material would disrupt the normal function of essential genes. Efficient translation of the encoded protein also does not require an external promoter sequence, again avoiding possible deleterious side effects. However, one problem with ribonucleic acid-based gene therapy is that ribonucleic acid is far less stable than DNA, especially when it reaches the cytoplasm of the cell and is exposed to degrading enzymes. For example, the presence of a hydroxyl group on the second carbon of the sugar moiety in the mRNA can result in steric hindrance, preventing the mRNA from forming a more stable DNA duplex, thereby making the mRNA more susceptible to hydrolytic degradation. In view of this, ribonucleic acids are typically encapsulated in lipid particles (e.g., liposomes, solid lipid particles, etc.) to protect them from extracellular RNase degradation while facilitating cellular uptake and endosomal escape. Unfortunately, however, their use in many applications remains problematic. For example, it is difficult to controllably deliver nucleic acid-encapsulated lipid particles over a sustained period of time. One of the reasons for this difficulty is that the lipids used in the particles tend to have relatively low melting points, making it difficult to incorporate the lipids into the processes and polymeric materials used to form most conventional implantable medical devices.
Thus, there remains a need for implantable delivery devices capable of delivering encapsulated nucleic acid particles over a sustained period of time.
Disclosure of Invention
According to one embodiment of the present invention, an implantable medical device is disclosed. The device includes particles dispersed within a polymer matrix. The particles comprise a carrier component comprising a carrier and encapsulating a nucleic acid, wherein the polymer matrix comprises an ethylene vinyl acetate copolymer. The ratio of the melting temperature of the ethylene-vinyl acetate copolymer to the melting temperature of the support is about 2 ℃ per DEG C or less.
Other features and aspects of the present invention will be set forth in more detail below.
Drawings
A full and enabling disclosure of the present invention, including the best mode thereof, directed to one of ordinary skill in the art, is set forth more particularly in the remainder of the specification, including reference to the accompanying figures, in which:
FIG. 1 is a perspective view of one embodiment of an implantable medical device of the present invention;
FIG. 2 is a cross-sectional view of the implantable medical device of FIG. 1;
FIG. 3 is a perspective view of another embodiment of an implantable medical device of the present invention; and
fig. 4 is a cross-sectional view of the implantable medical device of fig. 3.
Repeated use of reference characters in the specification and drawings is intended to represent the same or analogous features or elements of the invention.
Detailed Description
It is to be understood by one of ordinary skill in the art that the present discussion is a description of exemplary embodiments only, and is not intended as limiting the broader aspects of the present invention.
In general, the present invention is directed to an implantable medical device capable of delivering nucleic acids to a patient (e.g., a human, pet, farm animal, horse race, etc.) over a sustained period of time to help prevent and/or treat a disorder, disease, and/or cosmetic condition of the patient. The implantable medical device comprises nucleic acid encapsulated particles dispersed within a polymer matrix comprising one or more ethylene vinyl acetate copolymers. The weight ratio of polymer matrix to particles is typically from about 1 to about 10, in some embodiments from about 1.1 to about 8, in some embodiments from about 1.2 to about 6, and in some embodiments, from about 1.5 to about 4. For example, in one embodiment, an implantable medical device may include a drug release layer. The nucleic acid-encapsulated particles can constitute from about 1wt.% to about 60wt.%, in some embodiments from about 5wt.% to about 50wt.%, and in some embodiments, from about 10wt.% to about 45wt.% of the drug-releasing layer; while the polymer matrix may constitute from about 40wt.% to about 99wt.%, in some embodiments from about 50wt.% to about 95wt.%, and in some embodiments, from about 55wt.% to about 90wt.% of the drug release layer.
The particles comprise a carrier component comprising one or more carrier types and/or one or more carrier layers, such as peptides, proteins, carbohydrates (e.g., saccharides), polymers, lipids, and the like. In one embodiment, for example, the carrier may be a lipid, which refers generally to small molecules having hydrophobicity or amphiphilicity, such as fats, waxes, sterol-containing metabolites, vitamins, fatty acids, glycerolipids, glycerophospholipids, sphingolipids, glycolipids, polyketides, and prenyl lipids. Examples of such lipids may include, for example, phospholipids, such as alkylphosphocholine and/or fatty acid modified phosphocholine (e.g., 1, 2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) or 1, 2-distearoyl-sn-glycero-3-phosphocholine (DSPC)); cationic lipids such as 2, 2-diimine-4-dimethylaminoethyl- [1,3] -dioxolane (DLin-KC 2-DMA), diimine-methyl-4-dimethylaminobutyrate (DLin-MC 3-DMA), or di ((Z) -non-2-en-1-yl) 9- ((4- (dimethylamino) -butyryl) oxy) heptadecane diacid ester (L319); auxiliary lipids (e.g., fatty acids); structural lipids (e.g., sterols); polyethylene glycol (PEG) conjugated lipids, and the like, as well as combinations of any of the foregoing. Regardless, at least one carrier (e.g., lipid) used in the carrier component is selected to have a melting temperature similar to or higher than the melting temperature of the ethylene-vinyl acetate copolymer within the polymer matrix. Indeed, in certain embodiments, multiple carriers or even all carriers within a carrier component may be selected to have a melting temperature similar to or higher than the melting temperature of the ethylene-vinyl acetate copolymer within the polymer matrix. In this way, the encapsulated particles may remain stable at or near the melt processing temperature of the ethylene-vinyl acetate copolymer used in the polymer matrix, which is typically higher than the melt temperature of such copolymers. For example, the ratio of the melting temperature (c) of the ethylene-vinyl acetate copolymer within the polymer matrix to the melting temperature (c) of the carrier (e.g., lipid) within the carrier component may be about 2 c/c or less, in some embodiments about 1.8 c/c or less, in some embodiments about 0.1 c/c to about 1.6 c/c, in some embodiments about 0.2 c/c to about 1.5 c/c, and in some embodiments, about 0.4 c/c to about 1.2 c/c. For example, the melting temperature of the ethylene vinyl acetate copolymer and the resulting polymer matrix may be, for example, from about 20 ℃ to about 100 ℃, in some embodiments from about 25 ℃ to about 80 ℃, in some embodiments from about 30 ℃ to about 70 ℃, in some embodiments from about 35 ℃ to about 65 ℃, and in some embodiments, from about 40 ℃ to about 60 ℃ as determined according to ASTM D3418-15. The melting temperature of the carrier (e.g., lipid) may likewise be from about 25 ℃ to about 105 ℃, in some embodiments from about 30 ℃ to about 85 ℃, in some embodiments from about 35 ℃ to about 75 ℃, in some embodiments from about 40 ℃ to about 70 ℃, and in some embodiments, from about 45 ℃ to about 65 ℃.
Various embodiments of the present invention will now be described in more detail.
I.Polymer matrix
As mentioned above, the polymer matrix contains at least an ethylene-vinyl acetate copolymer, which is generally derived from at least one ethylene monomer and at least one vinyl acetate monomer. The inventors have found that certain aspects of the copolymer can be selectively controlled to help achieve desired release characteristics. Example(s)For example, the vinyl acetate content of the copolymer may be selectively controlled to range from about 10wt.% to about 60wt.%, in some embodiments from about 20wt.% to about 60wt.%, in some embodiments from about 25wt.% to about 55wt.%, in some embodiments from about 30wt.% to about 50wt.%, in some embodiments from about 35wt.% to about 48wt.%, and in some embodiments, from about 38wt.% to about 45wt.% of the copolymer. Conversely, the ethylene content of the copolymer may likewise range from about 40wt.% to about 80wt.%, 45wt.% to about 75wt.%, in some embodiments from about 50wt.% to about 80wt.%, in some embodiments from about 52wt.% to about 65wt.%, and in some embodiments, from about 55wt.% to about 62wt.%. Such comonomer content can help, among other things, achieve a controlled sustained release profile of the nucleic acid-encapsulated particles while also having a relatively low melting temperature that is substantially more similar to the melting temperature of the carrier used in the particles. The melt flow index of the ethylene-vinyl acetate copolymer and resulting polymer matrix may also range from about 0.2g/10min to about 100g/10min, in some embodiments from about 5g/10min to about 90g/10min, in some embodiments from about 10g/10min to about 80g/10min, and in some embodiments, from about 30g/10min to about 70g/10min, as determined according to ASTM D1238-20 at a temperature of 190 ℃ and a load of 2.16 kilograms. The ethylene-vinyl acetate copolymer may also have a density ranging from about 0.90 grams/cc to about 1.00 grams/cc (g/cm) as determined according to ASTM D1505-18 3 ) In some embodiments about 0.910g/cm 3 To about 0.980g/cm 3 And in some embodiments about 0.940g/cm 3 To about 0.970g/cm 3 . Particularly suitable examples of ethylene-vinyl acetate copolymers that may be used include: available under the trade name Celanese (Celanese)(e.g.4030 AC); available under the trade name +.>(e.g.)>40W); a trade name obtainable from Arkema (Arkema) is +.>Copolymers such as EVATANE 40-55.
In certain embodiments, it may also be desirable to use a blend of an ethylene-vinyl acetate copolymer and a hydrophobic polymer (e.g., an ethylene-vinyl acetate copolymer) such as described below, such that the blend as a whole and the polymer matrix have melt temperatures and/or melt flow indices within the ranges described above. For example, the polymer matrix may comprise a first ethylene copolymer and a second ethylene copolymer, wherein the second ethylene copolymer has a melting temperature that is higher than the melting temperature of the first ethylene copolymer. Also the melt flow index of the second ethylene copolymer may be the same as, lower than or higher than the corresponding melt flow index of the first ethylene copolymer. The first ethylene-vinyl acetate copolymer may have a melting temperature, for example, of from about 20 ℃ to about 60 ℃, in some embodiments from about 25 ℃ to about 55 ℃, and in some embodiments, from about 30 ℃ to about 50 ℃, as determined, for example, according to ASTM D3418-15; and/or a melt flow index of from about 40g/10min to about 900g/10min, in some embodiments from about 50g/10min to about 500g/10min, and in some embodiments, from about 55g/10min to about 250g/10min, as determined according to ASTM D1238-20 at a temperature of 190 ℃ and a load of 2.16 kilograms. The second ethylene-vinyl acetate copolymer may likewise have a melting temperature of from about 50 ℃ to about 100 ℃, in some embodiments from about 55 ℃ to about 90 ℃, and in some embodiments, from about 60 ℃ to about 80 ℃, for example, as determined according to ASTM D3418-15; and/or a melt flow index of from about 0.2g/10min to about 55g/10min, in some embodiments from about 0.5g/10min to about 50g/10min, and in some embodiments, from about 1g/10min to about 40g/10min, as determined according to ASTM D1238-20 at a temperature of 190 ℃ and a load of 2.16 kilograms. The first ethylene copolymer may constitute from about 20wt.% to about 80wt.%, in some embodiments from about 30wt.% to about 70wt.%, and in some embodiments, from about 40wt.% to about 60wt.% of the polymer matrix; and the second ethylene copolymer may likewise constitute from about 20wt.% to about 80wt.%, in some embodiments from about 30wt.% to about 70wt.%, and in some embodiments, from about 40wt.% to about 60wt.% of the polymer matrix. Blends of ethylene-vinyl acetate copolymers and other hydrophobic polymers such as those described below may also be used in the polymer matrix.
Any of a variety of techniques may generally be used to form ethylene-vinyl acetate copolymers having the desired characteristics known in the art. In one embodiment, the polymer is produced by copolymerizing ethylene monomer and vinyl acetate monomer in a high pressure reaction. Vinyl acetate may be produced by oxidizing butane to acetic anhydride and acetaldehyde, which may react together to form ethylene diacetate. Ethylene diacetate can then be thermally decomposed in the presence of an acid catalyst to form vinyl acetate monomers. Examples of suitable acid catalysts include aromatic sulfonic acids (e.g., benzenesulfonic acid, toluenesulfonic acid, ethylbenzene sulfonic acid, xylenesulfonic acid, and naphthalene sulfonic acid), sulfuric acid, and alkanesulfonic acids (e.g., as described in U.S. Pat. No. 2,425,389 to Oxley et al, U.S. Pat. No. 2,859,241 to Schnizer, and U.S. Pat. No. 4,843,170 to Isshiki et al). Vinyl acetate monomer can also be produced by reacting acetic anhydride with hydrogen in the presence of a catalyst other than acetaldehyde. The process converts directly from acetic anhydride and hydrogen to vinyl acetate without the need to produce ethylene diacetate. In yet another embodiment, vinyl acetate monomer may be produced by reacting acetaldehyde and ketene in the presence of a suitable solid catalyst (e.g., a perfluorosulfonic acid resin or zeolite).
In some cases, the ethylene vinyl acetate copolymer comprises the entire polymer content of the polymer matrix. However, in other cases, it may be desirable to include other polymers, such as other hydrophobic and/or hydrophilic polymers as described below. When used, such other polymers are typically required to constitute from about 0.001wt.% to about 30wt.%, in some embodiments from about 0.01wt.% to about 20wt.%, and in some embodiments, from about 0.1wt.% to about 10wt.% of the polymer content of the polymer matrix. In this case, the ethylene-vinyl acetate copolymer may constitute from about 70wt.% to about 99.999wt.%, in some embodiments from about 80wt.% to about 99.99wt.%, and in some embodiments, from about 90wt.% to about 99.9wt.% of the polymer content of the polymer matrix.
If desired, the polymer matrix may also contain one or more plasticizers to help lower the processing temperature, thereby allowing the use of higher melting copolymers without degrading the encapsulated particles. Suitable plasticizers can include, for example, fatty acids, fatty acid esters, fatty acid salts, fatty acid amides, organic phosphates, hydrocarbon waxes, and the like, as well as mixtures thereof. The fatty acid may generally be any saturated or unsaturated acid having a carbon chain length of about 8 to 22 carbon atoms, and in some embodiments, about 10 to about 18 carbon atoms. The acid may be substituted if desired. Suitable fatty acids may include, for example, lauric acid, myristic acid, behenic acid, oleic acid, palmitic acid, stearic acid, ricinoleic acid, capric acid, neodecanoic acid, hydrogenated tallow fatty acid, hydroxystearic acid, hydrogenated castor oil fatty acid, erucic acid, coconut fatty acid, and the like, and mixtures thereof. Fatty acid derivatives such as fatty acid amides, e.g., oleamide, erucamide, stearamide, ethylenebis (stearamide), and the like, may also be used; fatty acid salts (e.g., metal salts) such as calcium stearate, zinc stearate, magnesium stearate, iron stearate, manganese stearate, nickel stearate, cobalt stearate, and the like; fatty acid esters such as fatty acid esters of fatty alcohols (e.g., 2-ethylhexanol, monoethylene glycol, isotridecyl alcohol, propylene glycol, pentaerythritol, etc.), fatty acid esters of glycerol (e.g., castor oil, sesame oil, etc.), fatty acid esters of polyhydric phenols, sugar fatty acid esters, etc.; and mixtures of any of the foregoing. Hydrocarbon waxes, including paraffin waxes, polyolefin and oxidized polyolefin waxes, and microcrystalline waxes may also be used. Particularly suitable are acids, salts or amides of stearic acid, such as stearic acid, calcium stearate, pentaerythritol tetrastearate or N, N' -ethylenebisstearamide. When used, plasticizers generally constitute from about 0.05wt.% to about 1.5wt.%, and in some embodiments, from about 0.1wt.% to about 0.5wt.% of the polymer matrix.
II.Encapsulated particles
A.Nucleic acid
As described above, the nucleic acid-encapsulating particles are dispersed within a polymer matrix. As used herein, the term "nucleic acid" generally refers to a compound, such as a nucleoside, nucleotide, polynucleotide, or combination thereof, that comprises a nucleobase and an acidic moiety. "nucleoside" generally refers to a compound (also referred to herein as a "nucleobase") containing a sugar molecule (e.g., pentose or ribose) or derivative thereof in combination with an organic base (e.g., purine or pyrimidine) or derivative thereof. "nucleotide" generally refers to a nucleoside comprising a phosphate group. Modified nucleotides may be synthesized by any useful method (e.g., chemical, enzymatic, or recombinant) to include one or more modified or unnatural nucleosides. A polynucleotide may comprise one or more linked nucleoside regions. These regions may have variable backbone linkages. The bond may be a standard phosphodiester bond, in which case the polynucleotide will comprise a nucleotide region. For example, a polynucleotide may contain three or more nucleotides that are linear molecules, wherein adjacent nucleotides are linked to each other by phosphodiester bonds. The term "nucleic acid" also encompasses RNA and single-and/or double-stranded DNA. More specifically, the nucleic acid may be or may include, for example, ribonucleic acid (RNA), deoxyribonucleic acid (DNA), threose Nucleic Acid (TNA), ethylene Glycol Nucleic Acid (GNA), peptide Nucleic Acid (PNA), locked nucleic acid (LNA, including LNA having a β -D-ribose configuration, α -LNA having an α -L-ribose configuration (diastereomer of LNA), 2 '-amino-LNA having 2' -amino functionalization, and 2 '-amino-c-LNA having 2' -amino functionalization), ethylene Nucleic Acid (ENA), cyclohexene nucleic acid (CeNA), or chimera or a combination thereof.
The nucleic acid may be naturally occurring, for example in the context of a genome, transcript, mRNA, tRNA, rRNA, siRNA, snRNA, plasmid, cosmid, chromosome, chromatid or other naturally occurring nucleic acid molecule. In another aspect, the nucleic acid molecule may be a non-naturally occurring molecule, such as a recombinant DNA or RNA, an artificial chromosome, an engineered genome, or a fragment thereof, or a synthetic DNA, RNA, DNA/RNA hybrid, or include non-naturally occurring nucleotides or nucleosides. Nucleic acids can be purified from natural sources, produced using recombinant expression systems and optionally purified, chemically synthesized, and the like. Nucleic acids may also include nucleoside analogs, such as analogs having chemically modified bases or sugars, and backbone modifications. In some embodiments, the nucleic acid is or contains a natural nucleoside (e.g., adenosine, thymidine, guanosine, cytidine, uridine, deoxyadenosine, deoxythymidine, deoxyguanosine, and deoxycytidine); nucleoside analogs (e.g., 2-aminoadenosine, 2-thiothymidine, inosine, pyrrolopyrimidine, 3-methyladenosine, 5-methylcytidine, 2-aminoadenosine, C5-bromouridine, C5-fluorouridine, C5-iodouridine, C5-propynyl-uridine, C5-propynyl-cytidine, C5-methylcytidine, 2-aminoadenosine, 7-deadenosine, 8-oxoadenosine, 8-oxoguanosine, O (6) -methylguanine, and 2-thiocytosine); chemically modified bases; biologically modified bases (e.g., methylated bases); inserting a base; modified sugars (e.g., 2 '-fluororibose, ribose, 2' -deoxyribose, arabinose, and hexose); and/or modified phosphate groups (e.g., phosphorothioate and 5' -N-phosphoramidite linkages).
Modified nucleotide base pairing can be used and encompasses not only standard adenosine-thymine, adenosine-uracil or guanosine-cytosine base pairs, but also base pairs formed between nucleotides and/or modified nucleotides comprising non-standard or modified bases, wherein the arrangement of the hydrogen bond donor and hydrogen bond acceptor allows hydrogen bonding between a non-standard base and a standard base or between two complementary non-standard base structures. An example of such non-standard base pairing is base pairing between the modified nucleotide inosine and adenine, cytosine or uracil. Any combination of bases/sugars or linkers may be incorporated into the polynucleotides of the present disclosure.
In certain embodiments, the nucleic acid can be a polynucleotide (e.g., an RNA polynucleotide, such as an mRNA polynucleotide), wherein one or more nucleobases have been modified for therapeutic purposes. Indeed, in certain embodiments, polynucleotides (e.g., RNA polynucleotides, such as mRNA polynucleotides) comprising a combination of at least two (e.g., 2, 3, 4, or more) modified nucleobases may be used. For example, suitable modified nucleobases in polynucleotides may be modified cytosines, such as 5-methylcytosine, 5-methyl-cytidine (m 5C), N4-acetyl-cytidine (ac 4C), 5-halo-cytidine (e.g., 5-iodo-cytidine), 5-hydroxymethyl-cytidine (hm 5C), 1-methyl-pseudoisocytidine, 2-thio-cytidine (s 2C), 2-thio-5-methyl-cytidine, and the like; modified uridine such as 5-cyanouridine, 4' -thiouridine, pseudouridine (ψ), N1-methyl pseudouridine (m1ψ), N1-ethyl pseudouridine, 2-thiouridine (s 2U), 4' -thiouridine, 2-thio-1-methyl-1-deaza-pseudouridine, 2-thio-1-methyl-pseudouridine, 2-thio-5-aza-uridine, 2-thio-dihydro-pseudouridine, 2-thio-dihydro-uridine, 2-thio-pseudouridine, 4-methoxy-pseudouridine, 4-thio-1-methyl-pseudouridine, 4-thio-pseudouridine, 5-aza-uridine, dihydro-pseudouridine, 5-methyl-uridine (mo 5U), 5-methoxy-uridine, 2' -O-methyl-uridine and the like; modified guanosine such as α -thioguanosine, inosine (I), 1-methyl-inosine (m 1I), huoreside (imG), methyl huoreside (mimG), 7-deaza-guanosine, 7-cyano-7-deaza-guanosine (preQO), 7-aminomethyl-7-deaza-guanosine (preQ 1), 7-methyl-guanosine (m 7G), 1-methyl-guanosine (m 1G), 8-oxo-guanosine, 7-methyl-8-oxo-guanosine, and the like; modified adenine such as α -thioadenosine, 7-deaza-adenosine, 1-methyl-adenosine (m 1A), 2-methyl-adenine (m 2A), N6-methyl-adenosine (m 6A), 2, 6-diaminopurine, etc.; and combinations thereof. In some embodiments, polynucleotides (e.g., RNA polynucleotides, such as mRNA polynucleotides) include a combination of at least two (e.g., 2, 3, 4, or more) of the above-described modified nucleobases.
In some embodiments, polynucleotides (e.g., RNA polynucleotides, such as mRNA polynucleotides) can be uniformly modified (e.g., fully modified, modified throughout the sequence) for a particular modification. For example, the polynucleotide may be homogeneously modified with 5-methyl-cytidine (m 5C), which means that all cytosine residues in the mRNA sequence are replaced with 5-methyl-cytidine (m 5C). Similarly, polynucleotides may be uniformly modified by replacing any type of nucleoside residue present in the sequence with a modification residue (e.g., any of the residues listed above).
In some embodiments, the polynucleotide functions as a messenger RNA (mRNA). "messenger RNA" (mRNA) generally refers to any polynucleotide that encodes a (at least one) polypeptide (naturally occurring, non-naturally occurring or modified amino acid polymer) and can be translated in vitro, in vivo, in situ, or ex vivo to produce the encoded polypeptide. The basic components of an mRNA molecule typically include at least one coding region, a 5' untranslated region (UTR), a 3' UTR, a 5' cap, and a poly-A tail. Polynucleotides can act as mRNAs but can be distinguished from wild-type mRNAs in terms of their functional and/or structural design features that are used to overcome the problems of efficient expression of polypeptides in existing therapies using nucleic acid-based therapies. The mRNA may contain at least one ribonucleic acid (RNA) polynucleotide(s) having an open reading frame encoding at least one polypeptide of interest. In some embodiments, the RNA polynucleotides of the mRNA encode 2-10, 2-9, 2-8, 2-7, 2-6, 2-5, 2-4, 2-3, 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, 3-4, 4-10, 4-9, 4-8, 4-7, 4-6, 4-5, 5-10, 5-9, 5-8, 5-7, 5-6, 6-10, 6-9, 6-8, 6-7, 7-10, 7-9, 7-8, 8-10, 8-9, or 9-10 polypeptides. In some embodiments, the RNA polynucleotides of the mRNA encode at least 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 polypeptides. In some embodiments, the RNA polynucleotide of the mRNA encodes at least 100 or at least 200 polypeptides.
In some embodiments, the nucleic acid is a therapeutic mRNA. As used herein, the term "therapeutic mRNA" refers to mRNA encoding a therapeutic protein. Therapeutic proteins mediate a variety of effects in a host cell or subject to treat a disease or to ameliorate signs and symptoms of a disease. For example, a therapeutic protein may replace a defective or abnormal protein, enhance the function of an endogenous protein, provide a new function to a cell (e.g., inhibit or activate endogenous cellular activity, or act as a delivery agent for another therapeutic compound (e.g., an antibody-drug conjugate)). The therapeutic mRNA can be used to treat a variety of diseases and conditions, such as bacterial infections, viral infections, parasitic infections, cell proliferation conditions, genetic conditions, and autoimmune conditions. The mRNA may be designed to encode a polypeptide of interest selected from any of a variety of target classes including, but not limited to: biological products, antibodies, vaccines, therapeutic proteins or peptides, cell penetrating peptides, secreted proteins, plasma membrane proteins, cytoplasmic or cytoskeletal proteins, intracellular membrane binding proteins, nucleoproteins, proteins associated with human diseases, targeting moieties or proteins encoded by the human genome for which therapeutic indications have not been determined yet but which have utility in the field of research and discovery.
Particularly suitable therapeutic mrnas are those comprising at least one ribonucleic acid (RNA) polynucleotide having an open reading frame encoding at least one antigenic polypeptide, wherein the RNA polynucleotide of the RNA comprises at least one chemical modification. The chemical modification may be, for example, pseudouridine, N1-methyl pseudouridine, N1-ethyl pseudouridine, 2-thiouridine, 4 '-thiouridine, 5-methylcytosine, 2-thio-1-methyl-1-deaza-pseudouridine, 2-thio-1-methyl-pseudouridine, 2-thio-5-aza-uridine, 2-thio-dihydro-pseudouridine, 2-thio-dihydro-uridine, 2-thio-pseudouridine, 4-methoxy-pseudouridine, 4-thio-1-methyl-pseudouridine, 4-thio-pseudouridine, 5-aza-uridine, dihydro-pseudouridine, 5-methyluridine, 5-methoxy-uridine and 2' -O-methyluridine.
Although not required, the particular nature of the nucleic acid may also be selected to help enhance its ability to be dispersed within a polymer matrix and delivered to a patient without significant degradation. For example, it may be desirable to co-deliver conventional RNA (e.g., mRNA) with self-amplifying RNA. For example, conventional mRNA typically comprises an open reading frame for a target antigen flanked by untranslated regions and having a terminal poly (a) tail. After transfection, they drive transient antigen expression. On the other hand, self-amplified mRNA is capable of directing its self-replication by synthesis of an RNA-dependent RNA polymerase complex to generate multiple copies of antigen-encoding mRNA, and expresses heterologous genes at high levels when introduced into the cytoplasm of a host cell. Circular RNAs (circrnas), which are single stranded RNAs joined end to end, may also be used. The target RNA may be circularized, for example, by reverse splicing of non-mammalian exogenous introns or by splint ligation of the 5 'and 3' ends of the linear RNA. Examples of suitable circrnas are described, for example, in U.S. patent publication No. 2019/0345503, which is incorporated herein by reference. Antisense RNA can also be used, which typically has bases carried on backbone subunits consisting of morpholino backbone groups, and wherein the backbone groups are linked by (charged and uncharged) inter-subunit linkages such that bases in the compound are capable of hybridizing to target sequences in RNA according to Watson-Crick (Watson-Crick) base pairing, thereby forming an RNA-oligonucleotide heteroduplex in the target sequence. Morpholino oligonucleotides having uncharged backbone linkages, including antisense oligonucleotides, are described in detail, for example, in U.S. patent nos. 5,698,685, 5,217,866, 5,142,047, 5,034,506, 5,166,315, 5,185,444, 5,521,063 and 5,506,337, which are incorporated herein by reference. Other exemplary antisense oligonucleotides are described in U.S. patent nos. 9,464,292, 10,131,910, 10,144,762, and 10,913,947, which are incorporated herein by reference.
In some cases, the nucleic acid may be an aptamer, such as an RNA aptamer. The RNA aptamer may be any suitable RNA molecule that can be used alone as a stand-alone molecule or can be integrated as part of a larger RNA molecule (e.g., RNA interference molecule) that has multiple functions. For example, the RNA aptamer may be located in an exposed region of the shRNA molecule (e.g., a loop region of the shRNA molecule) to allow the shRNA or miRNA molecule to bind to a surface receptor on the target cell. After internalization, it may then be processed by the RNA interference pathway of the target cell. Nucleic acids forming a nucleic acid aptamer can include naturally occurring nucleosides, modified nucleosides, naturally occurring nucleosides with hydrocarbon linkers (e.g., alkylene) and/or polyether linkers (e.g., PEG linkers) interposed between one or more nucleosides, modified nucleosides with hydrocarbon linkers or PEG linkers interposed between one or more nucleosides, or a combination thereof. In some embodiments, the nucleotide or modified nucleotide of the aptamer may be substituted with a hydrocarbon linker or a polyether linker. Suitable aptamers may be described, for example, in U.S. patent No. 9,464,293, which is incorporated herein by reference.
Nucleic acids fused to proteins may also be suitable for use in the present invention. For example, a protein (e.g., an antibody) may be covalently linked to an RNA (e.g., an mRNA). Such RNA-protein fusions can be synthesized by in vitro or in situ translation of an mRNA library containing peptide receptors linked to its 3' end. In one embodiment, after reading the entire open reading frame of information, the ribosome is paused upon reaching the designed pause site, and the acceptor moiety occupies the ribosome a site and accepts the nascent peptide chain of the peptidyl-tRNA from the P site to produce an RNA-protein fusion. Covalent linkage between the protein and RNA (in the form of an amide bond between the 3' end of the mRNA and the C-terminus of the protein encoded thereby) allows the genetic information in the protein to be recovered and amplified (e.g., by PCR) and then selected by reverse transcription of the RNA. Once the fusion is generated, selection or enrichment is based on the properties of the mRNA-protein fusion, or alternatively reverse transcription can be performed using mRNA templates attached to the protein to avoid the effect of single stranded RNA on selection. Examples of nucleic acids for such protein fusion are described, for example, in U.S. patent No. 6,518,018, which is incorporated herein by reference. Ribozymes (e.g., dnase and/or rnase) conjugated with nucleic acids having sequences that catalyze the cleavage of RNA may also be used, such as described in U.S. patent No. 10,155,946, which is incorporated herein by reference.
In addition to the single-stranded nucleic acids described above, a plurality of specific types of double-stranded nucleic acids may be used to help improve stability. In certain embodiments, circular DNA (cDNA) and plasmid nucleic acids (e.g., pDNA) can be used, which are closed circular forms of DNA. Examples of such nucleic acids are described, for example, in WO 2004/060277, which is incorporated herein by reference. Long double stranded DNA may also be used. For example, scaffold DNA origami (DNA origami) can be used, in which long single stranded DNA is folded into a specific shape by annealing the scaffold in the presence of a shorter oligonucleotide ("staple") containing a fragment or region of the scaffold complementarity sequence. Examples of such structures are described, for example, in U.S. patent publication nos. 2019/0142882 and 2018/0171386, which are incorporated herein by reference.
B.Carrier component
The molar ratio of carrier component to nucleic acid (e.g., mRNA) in the particles can vary, but is typically from about 2:1 to about 50:1, in some embodiments from about 5:1 to about 40:1, in some embodiments from about 10:1 to about 35:1, and in some embodiments, from about 15:1 to about 30:1.
As described above, the carrier component comprises a carrier, such as a peptide (e.g., RALA), a protein, a carbohydrate (e.g., a saccharide), a polymer (e.g., a dextran polymer, such as diethylaminoethyl-dextran; polyethyleneimine; poly (amino esters), aliphatic polyesters, such as polylactic acid, etc.), a lipid, etc., and combinations of any of the foregoing, such as a peptide/polymer mixture (e.g., RALA-PLA). In a particular embodiment, for example, the carrier component can be a lipid component that contains one or more lipids. The properties of such lipid particles may generally vary, as known to those skilled in the art. In one embodiment, for example, the lipid component is a lipid vesicle (e.g., a liposome) comprising one or more lipid types and/or one or more lipid layers. For example, liposomes typically comprise phospholipids which are capable of assembling into one or more lipid bilayers. The phospholipid has a phospholipid moiety and optionally one or more additional moieties (e.g., fatty acid moieties). The phospholipid moiety may include, for example, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, phosphatidic acid, 2-lysophosphatidylcholine, and sphingomyelin. When used, the fatty acid moiety may also include, for example, lauric acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, alpha-linolenic acid, erucic acid, phytanic acid, arachic acid, arachidonic acid, eicosapentaenoic acid, docosanoic acid, docosapentaenoic acid, docosahexaenoic acid, and the like. Non-natural species are also contemplated, including natural species having modifications and substitutions (including branching, oxidation, cyclization, and alkynes). For example, the phospholipids may be functionalized or crosslinked with one or more alkynes (e.g., one or more double bonds of the alkenyl group are substituted with a triple bond). Under appropriate reaction conditions, alkynyl groups can undergo copper-catalyzed cycloaddition upon exposure to azide. Such reactions can be used to functionalize the lipid bilayer of the nanoparticle composition to facilitate membrane permeation or cell recognition. Examples of suitable phospholipids may include, for example, alkylphosphocholines such as hexadecylthio-phosphorylcholine, tetradecylphosphocholine, hexadecylphosphocholine, behenyl phosphorylcholine, 1, 2-dicetyl-rac-glycerol-3-phosphorylcholine, DL- α -lysophosphatidylcholine-r-o-hexadecane, and the like; fatty acid modified phosphorylcholine such as 1, 2-distearoyl-sn-glycero-3-phosphorylcholine (DSPC), 1, 2-dioleoyl-sn-glycero-3-phosphorylcholine (DOPE), 1, 2-dioleoyl-sn-glycero-3-phosphorylcholine (DLPC), 1, 2-dimyristoyl-sn-glycero-phosphorylcholine (DMPC), 1, 2-dioleoyl-sn-glycero-3-phosphorylcholine (DOPC), 1, 2-dioleoyl-sn-glycero-3-phosphorylcholine (DPPC), 1, 2-dioleoyl-sn-glycero-phosphorylcholine (DUPC), 1, 2-dioleoyl-sn-glycero-3-phosphorylcholine (POPC), 1, 2-dioleoyl-sn-glycero-3-phosphorylcholine (18:dieetpc), 1-oleoyl-2-sterolyl-succinyl-sn-glycero-3-phosphorylcholine (mopc), 1, 2-dioleoyl-sn-glycero-3-phosphorylcholine (DPPC), 1, 2-dioleoyl-sn-glycero-3-phosphorylcholine (pdown), 1, 2-dioleoyl-sn-glycero-3-phosphorylcholine (POPC), 1, 2-dioleoyl-glycero-3-phosphorylcholine (POPC) 1, 2-bis-docosahexaenoic acid-sn-glycerol-3-phosphorylcholine, 1, 2-bis-phytanic acid-sn-glycerol-3-phosphate ethanolamine (ME 16.0 PE), 1, 2-distearoyl-sn-glycerol-3-phosphate ethanolamine, 1, 2-dioleoyl-sn-glycerol-3-phosphate ethanolamine, 1, 2-bis-oleoyl-sn-glycerol-3-phosphate ethanolamine, 1, 2-bis-arachidonoyl-sn-glycerol-3-phosphate ethanolamine, 1, 2-bis-docosahexaenoic acid-sn-glycerol-3-phosphate ethanolamine, 1, 2-dioleoyl-sn-glycerol-3-phosphate-rac- (1-glycerol) sodium salt (DOPG), sphingomyelin, and the like; and mixtures of any of the foregoing.
The lipid component of the vesicles may also include other types of lipids, if desired. For example, the lipid component may contain one or more structural lipids to help alleviate aggregation of other lipids in the particle. Examples of suitable structural lipids may include, for example, sterols; sterols such as cholesterol, stigmasterol (fecosterol), sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, phytosterol, and the like; glycoside alkaloids such as lycorine, lycopersicin, and the like; terpenoids, such as ursolic acid; tocopherols, such as alpha-tocopherol; hopane and stanol ester; and mixtures thereof. The lipid component may also include one or more PEG conjugated lipids to help improve the colloidal stability of the particles in a biological environment by reducing specific absorption of plasma proteins and forming a hydrated layer on the particles. Examples of suitable PEG conjugated lipids may include, for example, PEG-modified phosphatidylethanolamine, PEG-modified phosphatidic acid, PEG-modified ceramide, PEG-modified dialkylamine, PEG-modified diacylglycerol, PEG-modified dialkylglycerol, and the like, and mixtures thereof. For example, the PEG lipid can be (R-3- [ (omega-methoxy-poly (ethylene glycol) 2000) carbamoyl) ] -1, 2-dimyristoxypropyl-3-amine) (PEG-c-DOMG), PEG-distearoyl glycerol (PEG-DMG), PEG-1, 2-dipalmitoyl-sn-glycero-3-phosphorylcholine (PEG-DPPC), PEG-DLPE, PEG-DMPE, PEG-DSPE, and the like, and mixtures thereof. The PEG conjugated lipids can also be modified to include hydroxyl groups on the PEG chain to form PEG-OH lipids. As generally defined herein, a "PEG-OH lipid" (also referred to herein as a "hydroxy-pegylated lipid") is a pegylated lipid having one or more hydroxy (-OH) groups on the lipid. In certain embodiments, the PEG-OH lipid comprises one or more hydroxyl groups on the PEG chain. In certain embodiments, the PEG-OH or hydroxy-pegylated lipid comprises an-OH group at the end of the PEG chain.
A variety of techniques can be used to form lipid vesicles having nucleic acids encapsulated therein. For example, the nucleic acid may be first dissolved in an aqueous solvent, such as water or a biocompatible buffer solution (e.g., phosphate buffered saline, HEPES, TRIS, etc.). Organic solvents such as dimethyl sulfoxide (DMSO), methanol, ethanol, propanol, propylene glycol, butanol, isopropanol, pentanol, pentane, fluorocarbons (e.g., freon), ethers, and the like may also be used. Surfactants may optionally be used to aid in the dispersion of the agent in the solvent. Lipids are also dissolved in the solvent before, after, or with the nucleic acid. The nucleic acid and lipid may be mixed at a lipid to nucleic acid molar ratio of about 3:1 to about 100:1 or higher, in some embodiments about 3:1 to about 10:1, and in some embodiments, about 5:1 to about 7:1. Once dissolved in the solvent, the nucleic acid and lipid may be mixed using any known technique. One suitable technique includes sonication at a controlled temperature determined by the melting point of the lipid, such as with a probe or bath sonicator (e.g., a Branson tip sonicator). Homogenization is another method of breaking up large vesicles into smaller vesicles by means of shear energy. In a typical homogenization procedure, multilamellar vesicles are recycled by a standard emulsion homogenizer. Other suitable techniques may include vortexing, extrusion, microfluidization, homogenization, and the like. Extrusion through a film (e.g., small pore polycarbonate or asymmetric ceramic) may also be used. Typically, the suspension is circulated through the membrane one or more times until the desired size distribution is achieved. The vesicles may be extruded through a continuous membrane of smaller pore size to achieve a gradual decrease in size. Preferably, the vesicles have a size of about 0.05 microns to about 0.5 microns, and in some embodiments, about 0.05 microns to about 0.2 microns.
Once the preparation is completed, the vesicles may be dehydrated into a dry particulate form and then incorporated into the polymer matrix. For example, vesicles may be dehydrated under reduced pressure using standard drying equipment (e.g., freeze-drying or spray-drying) or equivalent apparatus. The lipid vesicles and their surrounding medium may also be frozen in liquid nitrogen prior to dehydration and then placed under reduced pressure. Spray drying may also be used to form dry particles.
In addition to lipid vesicles, other types of lipid particles can be used to encapsulate nucleic acids. For example, solid lipid particles may be used in certain embodiments of the invention. Generally, such solid particles are in the form of nanoparticles having an average diameter of from about 10 nanometers to about 1000 nanometers, in some embodiments from about 20 nanometers to about 800 nanometers, in some embodiments from about 30 nanometers to about 600 nanometers, and in some embodiments, from about 40 nanometers to about 300 nanometers, as determined, for example, by laser diffraction techniques. Similar to lipid vesicles, solid particles also contain a lipid component comprising one or more lipid types and/or one or more lipid layers.
In one embodiment, for example, the lipid component of the solid particles comprises a cationic lipid. Cationic lipids are amphiphilic molecules containing positively charged polar head groups and hydrophobic tail domains that spontaneously self-assemble into higher order aggregates in aqueous solution. Due to having cationic groups (e.g., amino groups), cationic lipids can electrostatically interact with negatively charged phosphate groups of nucleic acid molecules (e.g., mRNA) and allow entrapment of the nucleic acid molecules within the lipid nanoparticle. The positive charge of the cationic lipid also helps to promote association with negatively charged cell membranes to enhance cellular uptake, and can bind to negatively charged lipids to induce non-bilayer structures that promote intracellular delivery. It is understood that the term "cation" includes lipids having a net positive charge at physiological pH, or ionizable lipids that acquire a net positive charge at acidic pH but retain a neutral charge at physiological pH. Suitable cationic lipids may include anionic lipids having an amino group, such as 3- (didodecylamino) -N1, N1, 4-tri-dodecyl-1-piperazineethylamine (KL 10), N1- [2- (didodecylamino) ethyl ] N1, N4, N4-tri-dodecyl-1, 4-piperazinediethylamine (KL 22), 14, 25-ditridecyl-15,18,21,24-tetraza-trioctadecyl (KL 25), 1, 2-dioleyloxy-N, N-dimethylaminopropane (DLin-DMA), 2-dioleyl-4-dimethylaminomethyl- [1,3] -dioxolane (DLin-K-DMA), triacontanyl-6,9,28,31-tetraen-19-yl-4- (dimethylamino) butyrate (DLin-MC 3-DMA), 2-dioleyl-4- (2-dimethylaminoethyl) - [1,3] -dioxolane (DLin-KC 2-DMA), 1, 2-dioleyloxy-N, 2-dioleyloxy-4-dimethylaminomethyl- [1,3] -dioxolane (DLin-K-DMA), 2-dioleyl-6,9,28,31-tetraen-4- (dimethylamino) butanoate (DLin-MC 3-DMA), 2- [ (dioleyl-N, 3-dioleyl-N-3-dioleyl) -3- [ (3-methyl ] -3-dioleyl ] -N- (. Beta., 12Z) -octadecyl-9, 12-dien-1-yloxy ] propan-1-amine (Octyl-CLinDMA), (2R) -2- ({ 8- [ (3β) -cholest-5-en-3-yloxy ] Octyl } oxy) -N, N-dimethyl-3- [ (9Z-, 12Z) -octadecyl-9, 12-dien-1-yloxy ] propan-1-amine (Octyl-CLinDMA (2R)), and (2S) 2- ({ 8- [ (3β) -cholest 5-en-3-yloxy ] Octyl } oxy) -N, N-dimethyl-3- [ (9Z-, 12Z) -octadecyl-9, 12-dien-1-yloxy ] propan-1-amine (Octyl-CLinDMA (2S)). In addition, the cationic lipid may be a lipid comprising cyclic amine groups, such as 2, 2-diimine-4-dimethylaminoethyl- [1,3] -dioxolane (DLin-KC 2-DMA), diimine-methyl-4-dimethylaminobutyrate (DLin-MC 3-DMA) and/or di ((Z) -non-2-en-1-yl) 9- ((4- (dimethylamino) -butyryl) oxy) heptadecane diacid ester (L319).
Other examples of suitable cationic lipids may also include (20Z, 23Z) -N, N-dimethyldidecyl-20, 23-dien-10-amine, (17Z, 20Z) -N, N-dimethyldidecyl-17, 20-dien-9-amine, (1Z, 19Z) -N5N-dimethyldidodecyl-16, 19-dien-8-amine, (13Z, 16Z) -N, N-dimethyldidodecyl-13, 16-dien-5-amine, (12Z, 15Z) -N, N-dimethyldidecyl-12, 15-dien-4-amine, (14Z, 17Z) -N, N-dimethyldidecyl-14, 17-dien-6-amine, (15Z, 18Z) -N, N-dimethyldidecyl-15, 18-dien-10-amine, (18Z, 21Z) -N, N-dimethyldidecyl-18, 21-dien-10-amine, (12Z, 15Z) -N, N-dimethyldidecyl-12, 15-dien-4-amine, (14Z, 17-dien-6-amine, (18Z, 18Z) -N, 18-dimethyldidecyl-10-amine, (18Z ) -N, 18-dimethyldidecyl-9-dien-5-amine, (14Z, 17-N, 17-dimethyldidecyl-dien-9-amine, n-dimethylhexacosyl-17, 20-dien-7-amine, (16Z, 19Z) -N, N-dimethylhexadecyl-16, 19-dien-6-amine, (22Z, 25Z) -N, N-dimethylheptadecyl-22, 25-dien-10-amine, (21Z, 24Z) -N, N-dimethyltriacontyl-21, 24-dien-9-amine, (18Z) -N, N-dimethylheptadecyl-18-en-10-amine, (17Z) -N, N-dimethylhexadecyl-17-en-9-amine, (19Z, 22Z) -N, N-dimethyloctadecyl-19, 22-dien-7-amine, N-dimethylheptadecyl-10-amine, (20Z, 23Z) -N-ethyl-N-methyloctadecyl-20, 23-dien-10-amine, 1- [ (11Z, 14Z) -1-nonadecyl-11, 14-dien-1-yl-pyrrol-10-amine, (17Z) -N, N-dimethylheptadecyl-10-amine, (19, 22Z) -N, N-dimethylheptadecyl-10-amine, (20Z) -N-dimethylnonadecyl-10-amine, n-dimethylicosadecyl-17-en-10-amine, (24Z) -N, N-dimethyltricridecyl-24-en-10-amine, (20Z) -N, N-dimethyltricridecyl-20-en-10-amine, (22Z) -N, N-dimethyltricycloundecyl-22-en-10-amine, (16Z) -N, N-dimethylicosapenta-16-en-8-amine, (12Z, 15Z) -N, N-dimethyl-2-nonylheneicosyl-12, 15-dien-1-amine, (13Z, 16Z) -N, N-dimethyl-3-nonyldocosyl-13, 16-dien-1-amine, N, N-dimethyl-1- [ (1S, 2R) -2-octylcyclopropyl ] heptadecyl-N-8-amine, 1- [ (1S, 2R) -2-hexylcyclopropyl ] -N, N-dimethyldecadec-10-amine, N, N-dimethyl-1S, 2S-octyl-2- [ (1S, 2R) -2-octylcyclopropyl ] decadec-1, N- [ (1S, 16-dien-1-amine, n-dimethyl-1- [ (1S, 2S) -2- { [ (1R, 2R) -2-pentylcyclopropyl ] methyl } cyclopropyl ] nonadecyl-10-amine, N-dimethyl-1- [ (1S, 2R) -2-octylcyclopropyl- ] hexadecyl-8-amine, N-dimethyl- [ (1R, 2S) -2 undecyl cyclopropyl ] tetradecyl-5-amine, N-dimethyl-3- {7- [ (1S, 2R) -2-octylcyclopropyl ] heptyl } dodecyl-1-amine, 1- [ (1R, 2S) -2-heptylcyclopropyl ] -N, N-dimethyloctadecyl-9-amine, 1- [ (1S, 2R) -2-decylcyclopropyl ] -N, N-dimethylpentadecyl-6-amine, N-dimethyl-1- [ (1S, 2R)) -2-octylcyclopropyl ] pentadecyl-8-amine, R-N, N-dimethyl-1- [ (9Z, 12Z) -octadecyl-9, 12-oxy ] -3- (N-octyloxy) propane, n-dimethyl-1- [ (9Z, 12Z) -octadecyl-9, 12-dien-1-yloxy ] -3- (octyloxy) propan-2-amine, 1- {2- [ (9Z, 12Z) -octadecyl-9, 12-dien-1-yloxy ] -1- [ (octyloxy) methyl ] ethyl } pyrrolidine, (2S) -N, N-dimethyl-1- [ (9Z, 12Z) -octadecyl-9, 12-dien-1-yloxy ] -3- [ (5Z-) -oct-5-en-1-yloxy ] propan-2-amine, 1- {2- [ (9Z, 12Z) -octadecyl-9, 12-dien-1-yloxy ] -1- [ (octyloxy) methyl ] ethyl } azetidine, (2S) -1- (hexyloxy) -N, N-dimethyl-3- [ (9Z, 12Z) -octadecyl-9, 12-dien-1-yloxy ] propan-2-amine, (2S) -1- (heptyloxy) -N, N-dimethyl-9, 12-dien-1-yloxy ] propan-2-amine, n-dimethyl-1- (nonyloxy) -3- [ (9Z, 12Z) -octadecyl-9, 12-dien-1-yloxy ] propan-2-amine, N-dimethyl-1- [ (9Z) -octadecyl-9-en-1-yloxy ] -3- (octyloxy) propan-2-amine; (2S) -N, N-dimethyl-1- [ (6Z, 9Z, 12Z) -octadecyl-6, 9, 12-trien-1-yloxy ] -3- (octyloxy) propan-2-amine, (2S) -1- [ (11Z, 14Z) -eicosyl-11, 14-dien-1-yloxy ] -N, N-dimethyl-3- (pentyloxy) propan-2-amine, (2S) -1- (hexyloxy) -3- [ (11Z, 14Z) -eicosyl-11, 14-dien-1-yloxy ] -N, N-dimethylpropan-2-amine, 1- [ (11Z, 14Z) -eicosyl-11, 14-dien-1-yloxy ] -N, N-dimethyl-3- (octyloxy) propan-2-amine, 1- [ (13Z, 16Z) -docosyl-13, 16-dien-1-yloxy ] -N, N-dimethyl-3- (octyloxy) propan-2-amine, (2S) -1- (hexyloxy) -3- [ (11Z, 14Z) -eicosyl-1-yloxy ] -N, N-dimethylpropan-2-amine, 1-dien-1-yloxy ] -N, 14-dien-1-yloxy ] -N, N-dimethyl-3- (octyloxy) propan-2-amine, (2S) -1- [ (13Z) -docosan-13-en-1-yloxy ] -3- (hexyloxy) -N, N-dimethylpropan-yl-2-amine, 1- [ (13Z) -docosan-13-en-1-yloxy ] -N, N-dimethyl-3- (octyloxy) propan-2-amine, 1- [ (9Z) -hexadec-9-en-1-yloxy ] -N, N-dimethyl-3- (octyloxy) propan-2-amine, (2R) -N, N-dimethyl-H (1-methyloctyl) oxy ] -3- [ (9Z, 12Z) -octadecyl-9, 12-dien-1-yloxy ] propan-2-amine, (2R) -1- [ (3, 7-dimethyloctyl) oxy ] -N, N-dimethyl-3- [ (9Z, 12Z) -octadecyl-9, 12-dien-1-yloxy ] propan-2-amine, N-dimethyl-1- (octyloxy) -3- [ (9Z, 12-dien-1-yloxy ] propan-2-amine, N-dimethyl-1- (8-methylol) -2- { [ -yl ] propan-2-amine, N, N-dimethyl-1- { [8- (2-octylcyclopropyl) octyl ] oxy } -3- (octyloxy) propan-2-amine and (11E, 20Z, 23Z) -N, N-dimethyl-icosadecyl-11,20,2-trien-10-amine, or a pharmaceutically acceptable salt or stereoisomer thereof.
In addition to cationic lipids, the lipid component of the solid particles may also include other types of lipids. For example, the lipid component may contain a helper lipid, which is typically neutral or non-cationic at physiological pH. Such helper lipids may include phospholipids, fatty acids, glycerides (e.g., mono-, di-and tri-glycerides), isopentenol lipids, and the like, such as those described above. Suitable fatty acids may include fatty acids having at least 8 carbon atoms, such as unsaturated fatty acids (e.g., myristoleic acid, palmitoleic acid, hexadecenoic acid, oleic acid, elaidic acid, isooleic acid, linoleic acid, linolenic acid, alpha-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, docosahexaenoic acid, etc., or any cis/trans double bond isomer thereof), saturated fatty acids (e.g., caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachic acid, behenic acid, lignoceric acid, etc., or any cis/trans double bond isomer thereof), and combinations thereof. Particularly suitable helper lipids may include, for example, oleic acid or analogues thereof, as well as fatty acid modified phospholipids (e.g., 1, 2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and/or 1, 2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE)), as well as analogues of such compounds (e.g., amino acids or derivatives thereof) in which the phosphocholine moiety is replaced with a different zwitterionic group.
Structural lipids and/or PEG conjugated lipids as described above may also be used in the lipid component of the solid particles. Particularly suitable structural lipids are sterols, such as cholesterol. In a specific embodiment, the lipid component of the solid lipid particle comprises a combination of cationic lipids, helper lipids (e.g., phospholipids and/or fatty acids), and structural lipids (e.g., sterols). The cationic lipid may, for example, constitute from about 10mol.% to about 90mol.%, in some embodiments from about 15mol.% to about 80mol.%, and in some embodiments, from about 20mol.% to about 60mol.% of the lipid component. The auxiliary lipids may constitute from about 1mol.% to about 50mol.%, in some embodiments from about 2mol.% to about 40mol.%, and in some embodiments, from about 5mol.% to about 25mol.% of the lipid component. The structural lipids may likewise constitute from about 5mol.% to about 70mol.%, in some embodiments from about 15mol.% to about 65mol.%, and in some embodiments, from about 25mol.% to about 55mol.% of the lipid component. In some cases, the lipid component may be generally free of PEG conjugated lipids. In other cases, conjugated PEG may be used, for example, in an amount of about 0.1 to about 30mol.%, in some embodiments about 0.2 to about 20mol.%, and in some embodiments about 0.5 to about 15mol.% of the lipid component.
The formation of solid lipid particles encapsulating nucleic acids can be accomplished by a variety of methods known in the art. Examples of such methods are described in, for example, U.S. patent No. 5,795,587;7,655,468;7,993,672;8,492,359;8,771,728 and 8,956,572; publication No. 2004/0262223;2010/015218;2012/0225129;2012/0276209;2012/0302622;2013/0037977;2013/0156845;2014/0296322 and 2015/0209440, the contents of which are incorporated herein by reference. For example, a microfluidic mixer may be used to synthesize solid lipid particles. Exemplary microfluidic mixers may include, but are not limited to, slit interdigital micromixers and/or staggered chevron micromixers (SHMs). For example, in a micromixer, lipids and nucleic acids can be mixed together by inducing chaotic convection of the microstructure. According to the method, a fluid flow flows through channels in a herringbone pattern, causing a rotational flow and causing the fluids to collapse upon each other. The method may further comprise a surface for fluid mixing, wherein the surface changes orientation during fluid circulation. Once formed, the solid particles may be dehydrated prior to incorporation into the polymer matrix. For example, the particles may be dehydrated under reduced pressure using standard freeze-drying equipment or equivalent equipment. Spray drying may also be used. During spray drying, moisture may form a film around the particles, reducing the temperature below the external ambient temperature, thereby minimizing the likelihood of any lipid melting during drying. In addition, a variety of techniques (e.g., electrostatic methods) can be used to atomize the droplets and allow for the use of lower temperatures.
In the embodiments discussed above, lipid vesicles (e.g., liposomes) and solid lipid particles are formed primarily from the lipid component that encapsulates the nucleic acid. However, this is by no means necessary in the present invention. In certain embodiments, for example, mixed particles comprising a polymer component, a lipid component, and a nucleic acid may be used. Such mixed particles can combine the benefits and features of liposomes and conventional polymeric nanoparticles. For example, the mixed particles may comprise a core encapsulating the nucleic acid and comprising the polymer, an intermediate layer (e.g., a monolayer or bilayer) surrounding the core and comprising the lipid, and an outer layer comprising the PEG conjugated lipid. Suitable polymers may include, for example, biodegradable polymers such as aliphatic polyesters (e.g., polylactic acid), aliphatic-aromatic copolyesters, and the like. The middle and/or outer layer may comprise a combination of cationic lipids, helper lipids, and PEG conjugated lipids as described above.
III.Excipient
The drug release layer may also optionally contain one or more excipients, such as cell permeability enhancers, ribonucleic acid degradation inhibitors (e.g., RNAase and/or DNAse inhibitors), radiocontrast agents, hydrophilic compounds, compatibilizers, plasticizers, surfactants, cross-linking agents, glidants, colorants (e.g., chlorophyll, methylene blue, etc.), antioxidants, stabilizers, lubricants, other types of antimicrobial agents, preservatives, etc., to enhance properties and processability. When used, the optional excipients generally constitute from about 0.01wt.% to about 20wt.%, and in some embodiments, from about 0.05wt.% to about 15wt.%, and in some embodiments, from about 0.1wt.% to about 10wt.% of the drug release layer. In one embodiment, for example, a radiocontrast agent may be used to help ensure that the device can be detected in X-ray based imaging techniques (e.g., computed tomography, projection radiography, fluoroscopy, etc.). Examples of such agents include, for example, barium-based compounds, iodine-based compounds, zirconium-based compounds (e.g., zirconium dioxide), and the like. One specific example of such a reagent is barium sulfate. Other known antimicrobial and/or preservative agents may also be used to help prevent the surface growth and attachment of bacteria, such as metal compounds (e.g., silver, copper, or zinc), metal salts, quaternary ammonium compounds, and the like.
Cell permeability enhancers can also be used to facilitate delivery of nucleic acids. Examples of such enhancers may include, for example, tight-junction modifiers, cyclodextrins, trihydroxy salts (e.g., bile salts such as sodium glycocholate or sodium fusidate), surfactants (e.g., sodium lauryl sulfate, cetyltrimethylammonium bromide, lauryl betaine, polyoxyethylene sorbitan monopalmitate, and the like), saponins, fusidic acid and its derivatives, fatty acids and its derivatives (e.g., oleic acid, glycerol monooleate, sodium caprate, sodium laurate, and the like), pyrrolidones (e.g., 2-pyrrolidone), alcohols (e.g., ethanol), glycols (e.g., propylene glycol), azones (e.g., laurocapram), terpenes, chelating agents (e.g., EDTA), dendrimers, oxazolidines, dioxolanes (e.g., 2-n-nonyl-1, 3-dioxolane), lipids (e.g., phospholipids), and the like.
To help minimize the risk of nucleic acid degradation, ribonucleic acid inhibitors may be used. Representative inhibitors for this purpose may include, for example, anti-nuclease antibodies and/or non-antibody inhibitors. Suitable nuclease antibodies may be anti-ribonuclease antibodies or anti-deoxyribonuclease antibodies. The anti-ribonuclease antibody may be an antibody that inhibits one or more of the following ribonucleases or deoxyribonucleases: RNase A, RNase B, RNase C, RNase 1, RNase T1, micrococcus nuclease, S1 nuclease, mammalian ribonuclease 1 family, ribonuclease 2 family, mammalian angiogenin, RNase H family, RNase L, eosinophil RNase, messenger RNA ribonuclease (5 '-3' exonuclease, 3'-5' exonuclease), decapsulase, deaminase, E.coli endoribonuclease (RNase P, RNase III, RNase E, RNase I, I.sub.RNase HI, RNase HII, RNase M, RNase R, RNase IV, F; RNase P2, O, PIV, RNase N), E.coli ribonuclease (RNase II, PNPase, RNase D, RNase BN, RNase T, RNPH, oligoase, RNR), sa, RNase F1, ase U2, ase DNase, DNase 1, S1, and micrococcus nuclease. Suitable non-antibody nuclease inhibitors may likewise include, but are not limited to: diethyl pyrocarbonate, ethanol, formamide, guanidine thiocyanate, vanadyl ribonucleoside complex, diatomaceous earth (Macaloid), sodium Dodecyl Sulfate (SDS), proteinase K, heparin, hydroxylamine-oxy-copper ion, bentonite, ammonium sulfate, dithiothreitol (DTT), beta-mercaptoethanol, cysteine, dithioerythritol, urea, polyamines (spermidine, spermine), detergents (e.g., sodium dodecyl sulfate), tris (2-carboxyethyl) phosphine hydrochloride (TCEP), and the like. Chelating agents are also suitable non-antibody nuclease inhibitors because such compounds help bind cations (e.g., calcium, iron, etc.) that would otherwise lead to degradation. Chelating agents can include, for example, aminocarboxylic acids (e.g., ethylenediamine tetraacetic acid) and salts thereof, hydroxycarboxylic acids (e.g., citric acid, tartaric acid, ascorbic acid, etc.) and salts thereof, polyphosphoric acids (e.g., tripolyphosphoric acid, hexametaphosphate, etc.) and salts thereof, and the like. Desirably, the chelating agent is multidentate in that it is capable of forming multiple coordination bonds with the metal ion to reduce the likelihood of any free metal ion. In one embodiment, for example, a multidentate chelating agent containing two or more amino diacetic acid (sometimes referred to as iminodiacetic acid) groups, or salts thereof, may be used. An example of such a chelating agent is ethylenediamine tetraacetic acid (EDTA). Examples of suitable EDTA salts include disodium calcium EDTA, diammonium EDTA, disodium and dipotassium EDTA, trisodium and tripotassium EDTA, tetrasodium and tetrapotassium EDTA. Other examples of similar aminodiacetic acid chelating agents include, but are not limited to, ethylenediamine tetraacetic acid, (1, 2-cyclohexylenediamine tetraacetic acid (CyDTA), diethylenetriamine pentaacetic acid (DTPA), ethylenediamine tetraacetic acid, (hydroxyethyl) ethylenediamine triacetic acid (HEDTA), triethanolamine EDTA, triethylenetetramine hexaacetic acid (TTHA), 1, 3-diamino-2-hydroxypropane-N, N, N ', N ' -tetraacetic acid (DHPTA), methyliminodiacetic acid, propylenediamine tetraacetic acid, ethylenediiminodiimalonic acid (EDDM), 2' -bis (carboxymethyl) iminodiacetic acid (ISA), ethylenediiminodiidosuccinic acid (EDDS), and the like.
To help further control the release rate of the implantable medical device, hydrophilic compounds may also be incorporated into the water-soluble and/or swellable drug release layer, for example. When used, the weight ratio of hydrophilic compound to ethylene vinyl acetate copolymer within the drug delivery layer may range from about 0.25 to about 200, in some embodiments from about 0.4 to about 80, in some embodiments from about 0.8 to about 20, in some embodiments from about 1 to about 16, and in some embodiments, from about 1.2 to about 10. For example, such hydrophilic compounds may constitute from about 1wt.% to about 60wt.%, in some embodiments from about 2wt.% to about 50wt.%, and in some embodiments, from about 5wt.% to about 40wt.%, while ethylene-vinyl acetate copolymers generally constitute from about 40wt.% to about 99wt.%, in some embodiments, from about 50wt.% to about 98wt.%, and in some embodiments, from about 60wt.% to about 95wt.% of the drug release layer. Suitable hydrophilic compounds may include, for example, polymers, non-polymeric materials, such as fatty acids or salts thereof (e.g., stearic acid, citric acid, myristic acid, palmitic acid, linoleic acid, and the like, and salts thereof), biocompatible salts (e.g., sodium chloride, calcium chloride, sodium phosphate, and the like), hydroxy-functional compounds as described below, and the like. Examples of suitable hydrophilic polymers include, for example, sodium alginate, potassium alginate, calcium alginate, cellulose compounds (e.g., hydroxymethyl cellulose, carboxymethyl cellulose, ethyl cellulose, methyl cellulose, etc.), agar, gelatin, polyvinyl alcohol, polyalkylene glycols (e.g., polyethylene glycol), collagen, pectin, chitin, chitosan, poly-1-caprolactone, polyvinylpyrrolidone, poly (vinylpyrrolidone-co-vinyl acetate), polysaccharides, hydrophilic polyurethanes, polyhydroxyacrylates, dextran, xanthan gum, proteins, ethylene-vinyl alcohol copolymers, water soluble polysilanes and polysiloxanes, water soluble polyurethanes, and the like, and combinations thereof. Particularly suitable hydrophilic polymers are polyalkylene glycols, such as those having a molecular weight of from about 100 g/mol to 500,000 g/mol, in some embodiments from about 500 g/mol to 200,000 g/mol, and in some embodiments, from about 1000 g/mol to about 100,000 g/mol. Specific examples of such polyalkylene glycols include, for example, polyethylene glycol, polypropylene glycol, polytetramethylene glycol, polyepichlorohydrin, and the like.
One or more nonionic, anionic, and/or amphoteric surfactants may also be used to aid in the formation of a uniform dispersion. When used, such surfactants typically constitute from about 0.05wt.% to about 8wt.%, in some embodiments from about 0.1wt.% to about 6wt.%, and in some embodiments, from about 0.5wt.% to about 3wt.% of the film layer. Usually having hydrophobic groups (e.g. long-chain alkyl or alkylatedAryl) and hydrophilic chains (e.g., chains containing ethoxy and/or propoxy moieties) are particularly suitable. Some suitable nonionic surfactants that may be used include, but are not limited to, ethoxylated alkylphenols, ethoxylated and propoxylated fatty alcohols, polyethylene glycol ethers of methyl glucose, polyethylene glycol ethers of sorbitol, ethylene oxide-propylene oxide block copolymers, ethoxylated esters of fatty (C8-C18) acids, condensation products of ethylene oxide with long chain amines or amides, condensation products of ethylene oxide with alcohols, fatty acid esters, monoglycerides or diglycerides of long chain alcohols, and mixtures thereof. Particularly suitable nonionic surfactants may include ethylene oxide condensates of fatty alcohols, polyoxyethylene ethers of fatty acids, polyoxyethylene sorbitan fatty acid esters, and the like. The fatty component used to form such emulsifiers may be saturated or unsaturated, substituted or unsubstituted, and may contain from 6 to 22 carbon atoms, in some embodiments from 8 to 18 carbon atoms, and in some embodiments, from 12 to 14 carbon atoms. Sorbitan fatty acid esters (e.g., monoesters, diesters, triesters, etc.) modified with polyoxyethylene are a particularly useful class of nonionic surfactants. These materials are typically prepared by adding ethylene oxide to 1, 4-sorbitan esters. Addition polyoxyethylene converts lipophilic sorbitan ester surfactants to hydrophilic surfactants, which are typically soluble or dispersible in water. Such materials are under the trade name (e.g.)>80 or polyethylene (20) sorbitan monooleate) are commercially available.
IV.Device configuration
A.Drug release layer
As described above, the drug release layer may be formed from a polymer matrix, encapsulated particles, and optional excipients. The drug-releasing layer and/or the implantable medical device may have a variety of different geometries, such as cylindrical (rod), disc-shaped, annular, doughnut-shaped, spiral, elliptical, triangular, oval, etc. In one embodiment, for example, the drug-releasing layer and/or the implantable medical device may have a generally circular cross-sectional shape such that the overall structure is in the form of a cylinder (rod) or disc. In such embodiments, the drug release layer and/or the implantable medical device typically has a diameter of about 0.5 millimeters to about 50 millimeters, in some embodiments about 1 millimeter to about 40 millimeters, and in some embodiments, about 5 millimeters to about 30 millimeters. The length of the drug release layer and/or the implantable medical device may vary, but is typically in the range of about 1 to about 25 millimeters. For example, a cylindrical device may have a length of about 5 millimeters to about 50 millimeters, while a disc-shaped device may have a length of about 0.5 to about 5 millimeters.
The drug release layer may be formed by a variety of known techniques, such as by hot melt extrusion, compression molding (e.g., vacuum compression molding), injection molding, solvent casting, dip coating, spray coating, micro-extrusion, coacervation, and the like. In one embodiment, hot melt extrusion techniques may be used. Hot melt extrusion is typically a solvent-free process in which the components of the drug release layer (e.g., ethylene-vinyl acetate copolymer, nucleic acid, carrier component, optional excipients, etc.) can be melt blended and optionally shaped in a continuous manufacturing process to achieve consistent output quality at high production rates. This technique is particularly suitable for ethylene-vinyl acetate copolymers because the ethylene-vinyl acetate copolymers generally exhibit a relatively high degree of long chain branching and a broad molecular weight distribution. This combination of properties can result in shear thinning of the copolymer during extrusion, which helps to facilitate hot melt extrusion. In addition, the polar vinyl acetate comonomer units can act as "internal" plasticizers by inhibiting crystallization of the polyethylene segments. This can result in a decrease in the melting point of the copolymer, further enhancing its ability to process with the encapsulated particles.
In hot melt extrusion processes, melt blending typically occurs at a temperature similar to or even lower than the melting temperature of the carrier (e.g., lipid) used in encapsulating the particles. Melt blending may also be performed at a temperature similar to or slightly higher than the melting temperature of the ethylene-vinyl acetate copolymer. The ratio of the melt blending temperature to the melting temperature of the carrier in the encapsulated particles may be, for example, about 2 or less, in some embodiments about 1.8 or less, in some embodiments about 0.1 to about 1.6, in some embodiments about 0.2 to about 1.5, and in some embodiments about 0.4 to about 1.2. The melt blending temperature may be, for example, from about 30 ℃ to about 100 ℃, in some embodiments from about 40 ℃ to about 80 ℃, and in some embodiments, from about 50 ℃ to about 70 ℃. A variety of melt blending techniques may generally be used. For example, these components may be supplied individually or in combination to an extruder that includes at least one screw rotatably mounted and housed within a barrel (e.g., a cylindrical barrel). The extruder may be a single screw or twin screw extruder. For example, one embodiment of a single screw extruder may comprise a housing or barrel and a screw rotatably driven at one end by a suitable drive (typically including a motor and gearbox). Twin screw extruders comprising two separate screws may be used if desired. The configuration of the screw is not particularly critical and it may comprise any number and/or orientation of flights and channels known in the art. For example, screws typically contain a flight that forms a generally helical channel extending radially around the center of the screw. The feed section and the melt section may be defined along the length of the screw. The feed section is the input portion of the barrel into which the ethylene-vinyl acetate copolymer is added and/or the particles are encapsulated. The melt section is a phase change section in which the copolymer changes from a solid state to a liquid-like state. While the contours of these segments are not precisely defined in the manufacture of the extruder, it is within the ordinary skill of those in the art to reliably determine the feed segment and the melt segment in which the phase change from solid to liquid occurs. Although not required, the extruder may also have a mixing section adjacent the output end of the barrel and downstream of the melting section. If desired, one or more distributing and/or dispersing mixing elements may be used within the mixing section and/or melting section of the extruder. Dispersive mixers suitable for use in a single screw extruder may include, for example, saxon, dulmage, cavity Transfer (Cavity Transfer) mixers, and the like. Likewise, suitable dispersive mixers may include a vacuum-molded (Blister) ring, a Leroy/Maddock, a CRD mixer, and the like. Mixing can be further improved by using pins in the barrel that enable folding and reorientation of the polymer melt, such as those used in Buss Kneader extruders, cavity transfer mixers and vortex staggered pin (Vortex Intermeshing Pin) mixers, as is well known in the art.
The ratio of the length ("L") to the diameter ("D") of the screw can be selected, if desired, to achieve an optimal balance between throughput and component blending. For example, the L/D value may range from about 10 to about 50, in some embodiments from about 15 to about 45, and in some embodiments, from about 20 to about 40. For example, the length of the screw may be about 0.1 meters to about 5 meters, in some embodiments about 0.4 meters to about 4 meters, and in some embodiments, about 0.5 meters to about 2 meters. The screw diameter may likewise be from about 5 millimeters to about 150 millimeters, in some embodiments from about 10 millimeters to about 120 millimeters, and in some embodiments, from about 20 millimeters to about 80 millimeters. In addition to length and diameter, other aspects of the extruder may be selected to help achieve the desired degree of mixing. For example, the speed of the screw may be selected to achieve a desired residence time, shear rate, melt processing temperature, etc. For example, the screw speed may range from about 10 revolutions per minute to about 800 revolutions per minute ("rpm"), in some embodiments from about 20rpm to about 500rpm, and in some embodiments, from about 30rpm to about 400rpm. The apparent shear rate during melt blending may also range from about 100 seconds -1 Up to about 10000 seconds -1 In some embodiments about 500 seconds -1 Up to about 5000 seconds -1 And in some embodiments about 800 seconds -1 Up to about 1200 seconds -1 . Apparent shear rate equal to 4Q/pi R 3 Where Q is the volumetric flow rate of the polymer melt ("m) 3 S ") and R is the radius (" m ") of the capillary (e.g., extruder die) through which the molten polymer flows.
Once melt blended together, the resulting polymer composition may be extruded through an orifice (e.g., die) and formed into pellets, sheets, fibers, filaments, etc., which may thereafter be formed into a drug release layer using a variety of known forming methods, such as injection molding, compression molding, nano-molding, over-molding, blow molding, three-dimensional printing, etc. For example, injection molding may occur in two main phases, namely an injection phase and a holding phase. During the injection phase, the mold cavity is filled with the molten polymer composition. The hold phase is started after the injection phase is completed, where the dwell pressure is controlled to load additional material into the cavity and compensate for the volume shrinkage that occurs during cooling. After the injection is completed, it may be cooled. Once cooling is complete, the molding cycle is complete when the mold is opened and the part is ejected (e.g., with an ejector pin within the mold). Any suitable injection molding apparatus may generally be used in the present invention. In one embodiment, an injection molding apparatus may be used that includes a first mold frame and a second mold frame that together define a mold cavity having the shape of a drug release layer. The molding apparatus has a resin runner extending from an outer surface of the first mold half through the gate to the mold cavity. The polymer composition may be supplied to the resin runner using a variety of techniques. For example, the composition (e.g., in pellet form) may be fed to a feed hopper (not shown) coupled to an extruder barrel containing a rotating screw. As the screw rotates, the pellets move forward and are subjected to pressure and friction, thereby generating heat to melt the pellets. A cooling mechanism may also be provided to solidify the resin into the desired shape (e.g., disc shape, rod, etc.) of the drug release layer within the mold cavity. For example, the mold frame may include one or more cooling conduits through which a cooling medium flows to impart a desired mold temperature to the mold frame surface to solidify the molten material. The mold temperature (e.g., the temperature of the mold surface) may range from about 50 ℃ to about 120 ℃, in some embodiments from about 60 ℃ to about 110 ℃, and in some embodiments, from about 70 ℃ to about 90 ℃.
As described above, another suitable technique for forming a drug release layer of a desired shape and size is three-dimensional printing. In this process, the polymer composition may be incorporated into a printer cartridge that is readily adapted for use with a printer system. For example, the printer cartridge may contain a spool shaft or other similar device that carries the polymer composition. For example, when supplied in filament form, the spool may have a generally cylindrical edge around which the filaments are wound. The spool may likewise define a hole or shaft to allow it to be easily mounted to the printer during use. Any of a variety of three-dimensional printer systems may be used with the present invention. Particularly suitable printer systems are extrusion-based systems, which are commonly referred to as "fused deposition modeling" systems. For example, the polymer composition may be fed to a build chamber of a printhead containing rollers and a stage. The rollers may be movable along a vertical z-axis based on signals provided by a computer-operated controller. The gantry is a rail system that may be configured to move the printhead in a horizontal x-y plane within the build chamber based on signals provided by the controller. The printhead is supported by the gantry and is configured to print build structures on the roll in a layer-by-layer manner based on signals provided by the controller. For example, the printhead may be a dual head extrusion head.
Compression molding (e.g., vacuum compression molding) may also be used. In such a method, the layers of the device may be formed by heating and compressing the polymer compact into the desired shape under vacuum. More specifically, the method may include forming a polymer composition into a precursor conforming to a compression mold cavity, heating the precursor, and compression molding the precursor into a desired layer while heating the precursor. The polymer composition may be formed into a precursor by a variety of techniques, such as by dry powder mixing, extrusion, and the like. The temperature during compression may be from about 50 ℃ to about 120 ℃, in some embodiments from about 60 ℃ to about 110 ℃, and in some embodiments, from about 70 ℃ to about 90 ℃. The vacuum source may also apply negative pressure to the precursor during compression to help ensure that it retains an accurate shape. An example of such compression molding techniques is described in, for example, U.S. patent No. 10,625,444 to Treffer et al, the entire contents of which are incorporated herein by reference.
B.Film layer
In some cases, the implantable medical device may be multi-layered in that it has at least one membrane layer positioned immediately adjacent to the outer surface of the drug release layer (i.e., the "core"). The number of membrane layers may vary depending on the specific configuration of the device, the nature of the nucleic acid, and the desired release profile. For example, the device may have only one film layer. For example, referring to fig. 1 and 2, one embodiment of an implantable medical device 10 is shown, the implantable medical device 10 including a core 40, the core 40 having a generally circular cross-sectional shape and being elongated such that the resulting device is generally cylindrical in nature. The core 40 defines a peripheral surface 61 and the film layer 20 is circumferentially disposed about the peripheral surface 61. Similar to the core 40, the film layer 20 also has a generally circular cross-sectional shape and is elongated to cover the entire length of the core 40. During use of the device 10, nucleic acids can be released from the core 40 and pass through the membrane layer 20 such that the nucleic acids come out of the outer surface 21 of the device.
Of course, in other embodiments, the device may include multiple film layers. In the devices of fig. 1 and 2, for example, one or more additional membrane layers (not shown) may be provided on the membrane layer 20 to help further control the release of nucleic acids. In other embodiments, the device may be configured such that the die is positioned or sandwiched between separate film layers. For example, referring to fig. 3 and 4, one embodiment of an implantable medical device 100 is shown, the implantable medical device 100 comprising a core 140, the core 140 having a generally circular cross-sectional shape and being elongated such that the resulting device is substantially disc-shaped. The core 140 defines an upper outer surface 161 on which the first film layer 120 is positioned and a lower outer surface 163 on which the second film layer 122 is positioned. Similar to the tablet core 140, the first film layer 120 and the second film layer 122 also have a generally circular cross-sectional shape that generally covers the tablet core 140. If desired, the edges of the film layers 120 and 122 may also extend beyond the outer periphery of the core 140 so that the film layers may be sealed together to cover any exposed areas of the outer circumferential surface 170 of the core 140. During use of the device 100, nucleic acids can be released from the chip core 140 and pass through the first and second film layers 120 and 122 such that the nucleic acids come out of the outer surfaces 121 and 123 of the device. Of course, if desired, one or more additional membrane layers (not shown) may be provided on the first membrane layer 120 and/or the second membrane layer 122 to help further control the release of nucleic acids.
Regardless of the particular configuration used, the film layer typically comprises a film polymer matrix comprising a hydrophobic polymer. The film polymer matrix generally comprises from about 30wt.% to 100wt.%, in some embodiments from about 40wt.% to about 99wt.%, and in some embodiments, from about 50wt.% to about 90wt.% of the film layer. When multiple film layers are used, it is generally desirable that each film layer contain a film polymer matrix comprising such hydrophobic polymers. For example, the first film layer may comprise a first film polymer matrix and the second film layer may comprise a second film polymer matrix. In such embodiments, the first and second film polymer matrices each contain hydrophobic polymers that may be the same or different.
The polymers used in the film polymer matrix are generally hydrophobic in nature, so that they can maintain their structural integrity for a period of time when placed in an aqueous environment (e.g., in a mammalian body) and are stable enough to be stored for a long period of time prior to use. Examples of suitable hydrophobic polymers for this purpose may include, for example, polysiloxane polymers, polyolefins, polyvinylchlorides, polycarbonates, polysulfones, styrene-acrylonitrile copolymers, polyurethanes, polysiloxane polyether-polyurethanes, polycarbonate-polyurethanes, polysiloxane polycarbonate-polyurethanes, and the like, as well as combinations thereof. Of course, hydrophilic polymers coated or otherwise encapsulated with hydrophobic polymers are also suitable for use in the film polymer matrix. In certain embodiments, the film polymer matrix may comprise a semi-crystalline olefin copolymer. Such olefin copolymers may have a melting temperature in the range of, for example, from about 20 ℃ to about 100 ℃, in some embodiments from about 25 ℃ to about 80 ℃, in some embodiments from about 30 ℃ to about 70 ℃, in some embodiments from about 35 ℃ to about 65 ℃, and in some embodiments, from about 40 ℃ to about 60 ℃, e.g., as determined according to ASTM D3418-15. Such copolymers are typically derived from at least one olefin monomer (e.g., ethylene, propylene, etc.) and at least one polar monomer grafted onto the polymer backbone and/or incorporated as a polymer component (e.g., a block copolymer or a random copolymer). Suitable polar monomers include, for example, vinyl acetate, vinyl alcohol, maleic anhydride, maleic acid, (meth) acrylic acid (e.g., acrylic acid, methacrylic acid, etc.), acrylic esters (e.g., acrylic esters, methacrylic esters, ethyl acrylate, methyl methacrylate, ethyl methacrylate, etc.), and the like. A variety of such copolymers can generally be used in the polymer composition, such as ethylene-vinyl acetate copolymers, ethylene- (meth) acrylic acid polymers (e.g., ethylene-acrylic acid copolymers and partially neutralized ionomers of these copolymers, ethylene-methacrylic acid copolymers and partially neutralized ionomers of these copolymers, etc.), ethylene- (meth) acrylate polymers (e.g., ethylene-methyl acrylate copolymers, ethylene-ethyl acrylate copolymers, ethylene-butyl acrylate copolymers, etc.), and the like. Regardless of the particular monomer selected, the inventors have discovered that certain aspects of the copolymer can be selectively controlled to help achieve desired release characteristics. For example, the polar monomer content of the copolymer may be selectively controlled to range from about 20wt.% to about 60wt.%, in some embodiments from about 25wt.% to about 55wt.%, in some embodiments from about 30wt.% to about 50wt.%, in some embodiments from about 35wt.% to about 48wt.%, and in some embodiments, from about 38wt.% to about 45wt.% of the copolymer. Conversely, the olefin monomer content of the copolymer may likewise range from about 40wt.% to about 80wt.%, 45wt.% to about 75wt.%, in some embodiments from about 50wt.% to about 80wt.%, in some embodiments from about 52wt.% to about 65wt.%, and in some embodiments, from about 55wt.% to about 62wt.%.
The hydrophobic polymer used in the film polymer matrix may also be the same as or different from the ethylene-vinyl acetate copolymer used in the drug release layer. For example, in one embodiment, both the drug release layer (core) and the film layer use the same polymer (e.g., ethylene vinyl acetate copolymer). In other embodiments, the film layer may use a hydrophobic polymer (e.g., an alpha-olefin copolymer) having a lower melt flow index than the ethylene vinyl acetate copolymer used in the drug release layer. In addition, this may further aid in controlling nucleic acid from the deviceIs released. For example, the ratio of the melt flow index of the ethylene vinyl acetate copolymer used in the drug release layer to the melt flow index of the hydrophobic polymer used in the film layer may be from about 1 to about 20, in some embodiments from about 2 to about 15, and in some embodiments, from about 4 to about 12. The melt flow index of the hydrophobic polymer in the film layer may range, for example, from about 1g/10min to about 80g/10min, in some embodiments from about 2g/10min to about 70g/10min, and in some embodiments, from about 5g/10min to about 60g/10min, as determined according to ASTM D1238-13 at a temperature of 190 ℃ and a load of 2.16 kilograms. Examples of suitable ethylene-vinyl acetate copolymers that may be used include those available under the trade name from ceraness (Celanese) (e.g.,4030AC or 2861A).
The membrane layer used in the device may optionally comprise nucleic acid-encapsulated particles, such as described above, dispersed within a membrane polymer matrix. The nucleic acid and carrier components of the encapsulated particles in the film layer may be the same as or different from those used in the tablet core. Regardless, when such encapsulated particles are used in a film layer, it is generally desirable that the film layer generally contain an amount of particles such that the ratio of the concentration of encapsulated particles in the tablet core (wt.%) to the concentration of encapsulated particles in the film layer (wt.%) is greater than 1, in some embodiments about 1.5 or greater, and in some embodiments, about 1.8 to about 4. When used, the encapsulated particles typically constitute only about 1wt.% to about 40wt.%, in some embodiments about 5wt.% to about 35wt.%, and in some embodiments, about 10wt.% to about 30wt.% of the film layer. Of course, in other embodiments, the film layer is generally free of such nucleic acid-encapsulating particles prior to their release from the drug release layer. When multiple film layers are used, each film layer may generally contain the encapsulated particles in an amount such that the ratio of the weight percent of the encapsulated particles in the drug release layer to the weight percent of the particles in the film layer is greater than 1, in some embodiments about 1.5 or greater, and in some embodiments, from about 1.8 to about 4.
The film layer may also optionally contain one or more excipients as described above, such as radiocontrast agents, hydrophilic compounds, compatibilizers, plasticizers, surfactants, cross-linking agents, glidants, colorants (e.g., chlorophyll, methylene blue, etc.), antioxidants, stabilizers, lubricants, other types of antimicrobial agents, preservatives, etc., to provide performance and processability. When used, the optional excipients generally constitute from about 0.01wt.% to about 60wt.%, and in some embodiments, from about 0.05wt.% to about 50wt.%, and in some embodiments, from about 0.1wt.% to about 40wt.% of the film layer.
To help further control the release rate of the implantable medical device, for example, hydrophilic compounds such as those described above may also be incorporated into the membrane layer. When used, the weight ratio of hydrophobic polymer to hydrophilic compound within the film layer may range from about 0.25 to about 200, in some embodiments from about 0.4 to about 80, in some embodiments from about 0.8 to about 20, in some embodiments from about 1 to about 16, and in some embodiments, from about 1.2 to about 10. For example, such hydrophilic compounds may constitute from about 1wt.% to about 50wt.%, in some embodiments from about 2wt.% to about 40wt.%, and in some embodiments, from about 5wt.% to about 30wt.%, while hydrophobic polymers generally constitute from about 50wt.% to about 99wt.%, in some embodiments, from about 60wt.% to about 98wt.%, and in some embodiments, from about 70wt.% to about 95wt.% of the film layer.
In one embodiment, the membrane layer may contain a plurality of hydrophilic compounds in the form of water-soluble particles distributed within the membrane polymer matrix. In such embodiments, the particle size of the water-soluble particles may be controlled to help achieve a desired delivery rate. More specifically, the median diameter (D50) of the particles may be about 100 microns or less, in some embodiments about 80 microns or less, in some embodiments about 60 microns or less, and in some embodiments about 1 to about 40 microns, as determined, for example, using a laser scattering particle size distribution analyzer (e.g., LA-960 from Horiba). The particles may also have a narrow size distribution such that 90% or more by volume of the particles (D90) have a diameter within the above range. Such particles may be formed using a variety of different materials, such as fatty acids or salts thereof (e.g., stearic acid, citric acid, myristic acid, palmitic acid, linoleic acid, and the like, and salts thereof), cellulose compounds (e.g., hydroxymethyl cellulose, carboxymethyl cellulose, ethyl cellulose, methyl cellulose, and the like), biocompatible salts (e.g., sodium chloride, calcium chloride, sodium phosphate, and the like), hydroxy-functional compounds, and the like. In particularly suitable embodiments, the water-soluble particles generally contain a non-polymeric, hydroxy-functional compound. The term "hydroxy-functional" generally means that the compound contains at least one hydroxy group, and in some cases a plurality of hydroxy groups, for example 2 or more, in some embodiments 3 or more, in some embodiments 4 to 20, and in some embodiments 5 to 16 hydroxy groups. The term "non-polymeric" also generally means that the compound does not contain a substantial number of repeating units, for example, no more than 10 repeating units, in some embodiments no more than 5 repeating units, in some embodiments no more than 3 repeating units, and in some embodiments no more than 2 repeating units. In some cases, such compounds do not have any repeating units. Thus, such non-polymeric compounds have relatively low molecular weights, for example, from about 1 g/mol to about 650 g/mol, in some embodiments from about 5 g/mol to about 600 g/mol, in some embodiments from about 10 g/mol to about 550 g/mol, in some embodiments from about 50 g/mol to about 500 g/mol, in some embodiments from about 80 g/mol to about 450 g/mol, and in some embodiments, from about 100 g/mol to about 400 g/mol. Particularly suitable non-polymeric, hydroxy-functional compounds useful in the present invention include, for example, sugars and derivatives thereof, such as monosaccharides (e.g., dextran, fructose, galactose, ribose, deoxyribose, etc.); disaccharides (e.g., sucrose, lactose, maltose, etc.); sugar alcohols (e.g., xylitol, sorbitol, mannitol, maltitol, erythritol, galactitol, isomalt, inositol, lactitol, and the like); etc., and combinations thereof.
One or more nonionic, anionic and/or amphoteric surfactants, such as those described above, may also be used to help produce a uniform dispersion. When used, such surfactants typically constitute from about 0.05wt.% to about 8wt.%, and in some embodiments, from about 0.1wt.% to about 6wt.%, and in some embodiments, from about 0.5wt.% to about 3wt.% of the film layer.
The film layer may be formed using the same or different techniques as used to form the tablet core, such as by hot melt extrusion, injection molding, solvent casting, dip coating, spray coating, micro extrusion, coacervation, and the like. In one embodiment, hot melt extrusion techniques may be used. The core layer and the film layer may also be formed separately or simultaneously. For example, in one embodiment, the sheet core layer and the film layer are formed separately and then combined together using known bonding techniques, such as by stamping, heat sealing, adhesive bonding, and the like. Compression molding (e.g., vacuum compression molding) may also be used to form the implantable device. As described above, the drug release layer and the film layer, respectively, can be formed by heating and compressing the corresponding polymer under vacuum to compress the polymer into the desired shape. Once formed, the drug-releasing layer and the film layer may be laminated together to form a multi-layer precursor, which is thereafter compression molded in the manner described above to form the final implantable device.
V.Use of devices
By selectively controlling the specific nature of the device and its manner of formation, the resulting device can effectively sustain release of nucleic acid over an extended period of time. For example, the implantable medical device may release nucleic acid over a period of about 5 days or more, in some embodiments about 10 days or more, in some embodiments about 20 days to about 60 days, and in some embodiments about 25 days to about 50 days (e.g., about 30 days). Furthermore, the nucleic acid may be released in a controlled manner (e.g., zero order or near zero order) during the release period. For example, after a period of 15 days, the cumulative release rate of the implantable medical device may be from about 20% to about 70%, in some embodiments from about 30% to about 65%, and in some embodiments, from about 40% to about 60%. Likewise, after a period of 30 days, the cumulative release rate of the implantable medical device may still be from about 40% to about 85%, in some embodiments from about 50% to about 80%, and in some embodiments, from about 60% to about 80%. The "cumulative release rate" can be determined by dividing the amount of nucleic acid released at a particular time interval by the total amount of nucleic acid initially present and multiplying this value by 100.
Of course, the actual dosage level of nucleic acid delivered will vary depending on the particular nucleic acid used and the period of time for which it is intended to be released. The dosage level is generally high enough to provide a therapeutically effective amount of the nucleic acid to produce the desired therapeutic result, i.e., a level or amount effective to reduce or alleviate the symptoms of the disorder for which the nucleic acid is administered. The exact amount required will vary depending on the following factors: the subject being treated, the age and general condition of the subject to which the nucleic acid is to be delivered, the immune system capacity of the subject, the degree of effect desired, the severity of the condition being treated, the particular nucleic acid selected and the manner of administration of the composition, and the like. Suitable effective amounts can be readily determined by one skilled in the art. For example, an effective amount of nucleic acid delivered per day typically ranges from about 5 μg to about 200mg, in some embodiments from about 5 μg to about 100mg, and in some embodiments, from about 10 μg to about 1mg
The device may be implanted subcutaneously, orally, transmucosally, etc., using standard techniques. The route of delivery may be intrapulmonary, gastrointestinal, subcutaneous, intramuscular, access to the central nervous system (e.g., intrathecal), intraperitoneal, intra-organ, etc. In one embodiment, the implantable device may be particularly suitable for delivering nucleic acids for cancer treatment. In such embodiments, the device may be placed within, on, adjacent to, or near a tissue site of a tumor in a patient, such as a tumor of the pancreas, biliary system, gall bladder, liver, small intestine, colon, brain, lung, eye, and the like. The device may also be used with current systemic chemotherapy, external radiotherapy and/or surgery. The device may also be delivered intrathecally to treat and/or prevent a variety of different conditions, such as cancer, neurological diseases (e.g., neurodegenerative diseases, such as spinal muscular atrophy or amyotrophic lateral sclerosis), etc., and/or for pain management. In such embodiments, the device may be implanted within the spinal canal or directly into the intrathecal space (subarachnoid space) containing cerebrospinal fluid. For example, intrathecal administration may be accomplished by implanting the device into an Ommaya reservoir (a dome-shaped container placed under the scalp during surgery; the container holds the drug as it flows into the brain through a small tube) or directly into the cerebrospinal fluid located in the lower portion of the spine.
If desired, the device may be sealed within a package (e.g., a sterile blister package) prior to use. The materials and manner in which the package is sealed may vary as known in the art. For example, in one embodiment, the package may include a substrate that includes any number of layers (e.g., one or more, in some embodiments 1 to 4, and in some embodiments 1 to 3) necessary to achieve the desired level of protective properties. Typically, the substrate comprises a polymeric film, such as a film made of a polyolefin (e.g., ethylene copolymer, propylene homopolymer, etc.), a polyester (e.g., polyethylene terephthalate, polyethylene naphthalate, polybutylene terephthalate, etc.), a vinyl chloride polymer, a vinyl pyrimidyl polymer, an ionomer, etc., and combinations thereof. One or more sides of the film may be sealed together (e.g., heat sealed), such as at the peripheral edge, to form a cavity of the storable device. For example, a single film may be folded at one or more points and sealed along its perimeter to define a cavity in which the device is placed. To use the device, the package may be opened, for example by breaking the seal, and the device may then be removed and implanted in the patient.
Test method
The release of nucleic acid (e.g., mRNA) can be determined using in vitro methods. More specifically, the implantable device sample may be placed in 150 milliliters of aqueous sodium azide solution. The solution can be placed in 250 ml of ultraviolet-proofIn a bottle. The bottle may then be placed in a temperature controlled water bath and continuously shaken at 100 rpm. The temperature can be maintained at 37 ℃ by this release experiment to simulate in vivo conditions. Samples can be taken at regular time intervals by completely replacing the sodium azide aqueous solution. The concentration of nucleic acid in the solution can be determined by ultraviolet-visible absorption spectroscopy using a Cary 1 beam splitter. From this data, the amount of nucleic acid released per sampling interval (micrograms/hour) can be calculated and plotted over time (hours). Furthermore, the cumulative release rate of nucleic acid can also be calculated as a percentage by dividing the amount of nucleic acid released at each sampling interval by the total amount of nucleic acid initially present and multiplying this value by 100. The percentage is then plotted over time (hours).
These and other modifications and variations to the present invention may be practiced by those of ordinary skill in the art, without departing from the spirit and scope of the present invention. Further, it should be understood that aspects of the various embodiments may be interchanged both in whole or in part. Furthermore, those of ordinary skill in the art will appreciate that the foregoing description is by way of example only, and is not intended to limit the invention so further described in such appended claims.
Claims (50)
1. An implantable medical device comprising particles dispersed within a polymer matrix, wherein the particles comprise a carrier component, the carrier component comprising a carrier and encapsulating a nucleic acid, and wherein the polymer matrix comprises an ethylene-vinyl acetate copolymer, wherein the ratio of the melting temperature of the ethylene-vinyl acetate copolymer to the melting temperature of the carrier is about 2 ℃ per degree c or less.
2. The implantable medical device of claim 1, wherein the weight ratio of the polymer matrix to the particles is from about 1 to about 10.
3. The implantable medical device of claim 1, wherein the ethylene-vinyl acetate copolymer has a melting temperature of about 20 ℃ to about 100 ℃ as determined according to ASTM D3418-15.
4. The implantable medical device of claim 1, wherein the carrier has a melting temperature of about 25 ℃ to about 105 ℃.
5. The implantable medical device of claim 1, wherein the carrier component has a melting temperature of about 25 ℃ to about 105 ℃.
6. The implantable medical device of claim 1, wherein the ethylene-vinyl acetate copolymer comprises the entire polymer content of the polymer matrix.
7. The implantable medical device of claim 1, wherein the polymer matrix further comprises a plasticizer.
8. The implantable medical device of claim 1, wherein the polymer matrix further comprises a hydrophobic polymer.
9. The implantable medical device of claim 8, wherein the polymer matrix comprises a first ethylene vinyl acetate copolymer and a second ethylene vinyl acetate copolymer.
10. The implantable medical device of claim 1, wherein the copolymer has a vinyl acetate content of about 10wt.% to about 60wt.%.
11. The implantable medical device of claim 1, wherein the ethylene-vinyl acetate polymer has a melt flow index of about 0.2 g/10 min to about 100 g/10 min as determined according to ASTM D1238-20 at a temperature of 190 ℃ and a load of 2.16 kg.
12. The implantable medical device of claim 1, wherein the nucleic acid comprises ribonucleic acid.
13. The implantable medical device of claim 12, wherein the ribonucleic acid comprises mRNA.
14. The implantable medical device of claim 13, wherein the mRNA comprises a therapeutic mRNA comprising at least one ribonucleic acid polynucleotide having an open reading frame encoding at least one antigenic polypeptide.
15. The implantable medical device of claim 1, wherein the molar ratio of the carrier component to the nucleic acid is from about 2:1 to about 50:1.
16. The implantable medical device of claim 1, wherein the carrier is a peptide, protein, carbohydrate, lipid, polymer, or combination thereof.
17. The implantable medical device of claim 1, wherein the carrier is a lipid.
18. The implantable medical device of claim 17, wherein the particles are lipid vesicles containing a lipid component comprising phospholipids.
19. The implantable medical device of claim 18, wherein the phospholipid comprises alkylphosphocholines.
20. The implantable medical device of claim 18, wherein the lipid component further comprises a structural lipid, a PEG conjugated lipid, or a combination thereof.
21. The implantable medical device of claim 17, wherein the particles are solid lipid particles containing a lipid component.
22. The implantable medical device of claim 21, wherein the lipid component comprises a cationic lipid.
23. The implantable medical device of claim 22, wherein the lipid component further comprises a helper lipid, a structural lipid, a PEG conjugated lipid, or a combination thereof.
24. The implantable medical device of claim 23, wherein the auxiliary lipid comprises a fatty acid having a fatty acid chain of at least 8 carbons.
25. The implantable medical device of claim 23, wherein the helper lipid comprises a phospholipid having a phospholipid moiety and optionally a fatty acid moiety.
26. The implantable medical device of claim 23, wherein the structural lipid comprises a sterol.
27. The implantable medical device of claim 21, wherein the solid particles have an average diameter of about 10 nanometers to about 1000 nanometers.
28. The implantable medical device of claim 1, wherein the device has a generally circular cross-sectional shape.
29. The implantable medical device of claim 28, wherein the device has a diameter of about 0.5 millimeters to about 50 millimeters.
30. The implantable medical device of claim 1, wherein the device is in the form of a cylinder.
31. The implantable medical device of claim 1, wherein the device is in the form of a disc.
32. The implantable medical device of claim 1, wherein the drug release layer further comprises a ribonucleic acid degradation inhibitor.
33. The implantable medical device of claim 32, wherein the ribonucleic acid inhibitor comprises an anti-ribonuclease antibody.
34. The implantable medical device of claim 32, wherein the ribonucleic acid inhibitor comprises a chelator.
35. The implantable medical device of claim 1, wherein the drug release layer further comprises a cell permeability enhancer.
36. The implantable medical device of claim 1, wherein the polymer matrix further comprises a hydrophilic compound.
37. The implantable medical device of claim 36, wherein the hydrophilic compound comprises a hydrophilic polymer.
38. The implantable medical device of claim 37, wherein the hydrophilic polymer comprises sodium alginate, potassium alginate, calcium alginate, carboxymethyl cellulose, agar, gelatin, polyvinyl alcohol, polyalkylene glycol, collagen, pectin, chitin, chitosan, poly-1-caprolactone, polyvinylpyrrolidone, poly (vinylpyrrolidone-co-vinyl acetate), polysaccharides, hydrophilic polyurethanes, polyhydroxyacrylates, dextran, xanthan gum, hydroxypropyl cellulose, methylcellulose, proteins, ethylene-vinyl alcohol copolymers, water-soluble polysilanes, water-soluble polysiloxanes, water-soluble polyurethanes, or combinations thereof.
39. The implantable medical device of claim 1, wherein the device comprises a drug release layer, wherein the drug release layer comprises the particles and the polymer matrix.
40. The implantable medical device of claim 39, wherein the particles comprise from about 1wt.% to about 60wt.% of the drug release layer and the polymer matrix comprises from about 40wt.% to about 99wt.% of the drug release layer.
41. The implantable medical device of claim 39, further comprising a membrane layer positioned adjacent an outer surface of the drug release layer.
42. The implantable medical device of claim 41, wherein the membrane layer is free of particles comprising a carrier component that contains a carrier and encapsulates a nucleic acid.
43. The implantable medical device of claim 41, wherein the membrane layer comprises a membrane polymer matrix comprising a hydrophobic polymer.
44. The implantable medical device of claim 43, wherein the hydrophobic polymer comprises an ethylene vinyl acetate copolymer.
45. The implantable medical device of claim 43, wherein the membrane polymer matrix is formed entirely of a hydrophobic polymer.
46. The implantable medical device of claim 43, wherein the membrane polymer matrix further comprises a hydrophilic compound.
47. A method for forming the implantable medical device of claim 1, the method comprising melt blending the particles and the polymer matrix in an extruder.
48. The method of claim 47, wherein the melt blending occurs at a temperature of about 30 ℃ to about 100 ℃.
49. The method of claim 47, wherein the extruder comprises a rotatable screw having a length and a diameter, wherein the ratio of the length to the diameter is from about 10 to about 50.
50. A method for preventing and/or treating a disorder, disease and/or cosmetic condition in a patient, the method comprising subcutaneously implanting the device of claim 1 into the patient.
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US202163179627P | 2021-04-26 | 2021-04-26 | |
US63/179,627 | 2021-04-26 | ||
PCT/US2022/022239 WO2022212300A1 (en) | 2021-03-30 | 2022-03-29 | Implantable medical device for the delivery of nucleic acid-encapsulated particles |
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